Substituted lactams as inhibitors of Abeta protein production

ABSTRACT

This invention relates to novel lactams of Formula (I):  
                 
having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer&#39;s disease and Down&#39;s Syndrome.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/005,573, filed Dec. 6, 2004, which is a continuation of U.S.application Ser. No. 10/685,031, filed on Oct. 14, 2003, which is acontinuation of U.S. application Ser. No. 09/832,455, filed Apr. 11,2001, U.S. Pat. No. 6,632,812, and claims benefit of U.S. ProvisionalApplication Ser. No. 60/196,549, filed Apr. 11, 2000 and are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel lactams having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Thesenovel compounds inhibit the processing of amyloid precursor protein and,more specifically, inhibit the production of Aβ-peptide, thereby actingto prevent the formation of neurological deposits of amyloid protein.More particularly, the present invention relates to the treatment ofneurological disorders related to β-amyloid production such asAlzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a degenerative brain disorder characterizedclinically by progressive loss of memory, temporal and localorientation, cognition, reasoning, judgment and emotionally stability.AD is a common cause of progressive dementia in humans and is one of themajor cause of death in the United States. AD has been observed in allraces and ethnic groups worldwide, and is a major present and futurehealth problem. No treatment that effectively prevents AD or reversesthe clinical symptoms and underlying pathophysiology is currentlyavailable (for review see Dennis J. Selkoe; Cell Biology of the amyloid(beta)-protein precursor and the mechanism of Alzheimer's disease, AnnuRev Cell Biol, 1994, 10: 373-403).

Histopathological examination of brain tissue derived upon autopsy orfrom neurosurgical specimens in effected individuals revealed theoccurrence of amyloid plaques and neurofibrillar tangles in the cerebralcortex of such patients. Similar alterations were observed in patientswith Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhagewith amyloidosis of the Dutch-type. Neurofibrillar tangles andnonmembrane-bound bundles of abnormal proteinaceous filaments andbiochemical and immunochemical studies led to the conclusion that theirprinciple protein subunit is an altered phosphorylated form of the tauprotein (reviewed in Selkoe, 1994).

Biochemical and immunological studies revealed that the dominantproteinaceous component of the amyloid plaque is an approximately 4.2kilodalton (kD) protein of about 39 to 43 amino acids. This protein wasdesignated Aβ, β-amyloid peptide, and sometimes β/A4; referred to hereinas Aβ. In addition to its deposition in amyloid plaques, Aβ is alsofound in the walls of meningeal and parenchymal arterioles, smallarteries, capillaries, and sometimes, venules. Aβ was first purified anda partial amino acid reported in 1984 (Glenner and Wong, Biochem.Biophys. Res. Commun. 120: 885-890). The isolation and sequence data forthe first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Compelling evidence accumulated during the last decade revealed that Aβis an internal polypeptide derived from a type 1 integral membraneprotein, termed β amyloid precursor protein (APP). β APP is normallyproduced by many cells both in vivo and in cultured cells, derived fromvarious animals and humans. Aβ is derived from cleavage of β APP by asyet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has beenpostulated. They include β secretase(s), generating the N-terminus ofAβ, α secretase(s) cleaving around the 16/17 peptide-bond in Aβ, and γsecretases, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ playsa key role in the pathogenesis of AD. Firstly, Aβ is the major proteinfound in amyloid plaques. Secondly, Aβ is neurotoxic and may be causallyrelated to neuronal death observed in AD patients. Thirdly, missense DNAmutations at position 717 in the 770 isoform of β APP can be found ineffected members but not unaffected members of several families with agenetically determined (familiar) form of AD. In addition, several otherβ APP mutations have been described in familiar forms of AD. Fourthly,similar neuropathological changes have been observed in transgenicanimals overexpressing mutant forms of human β APP. Fifthly, individualswith Down's syndrome have an increased gene dosage of β APP and developearly-onset AD. Taken together, these observations strongly suggest thatAβ depositions may be causally related to the AD.

It is hypothesized that inhibiting the production of Aβ will prevent andreduce neurological degeneration, by controlling the formation ofamyloid plaques, reducing neurotoxicity and, generally, mediating thepathology associated with Aβ production. One method of treatment methodswould therefore be based on drugs that inhibit the formation of Aβ invivo. Methods of treatment could target the formation of Aβ through theenzymes involved in the proteolytic processing of β amyloid precursorprotein. Compounds that inhibit β or γ secretase activity, eitherdirectly or indirectly, could control the production of Aβ.Advantageously, compounds that specifically target γ secretases, couldcontrol the production of A{tilde over (β)} Such inhibition of β or γsecretases could thereby reduce production of A

which, thereby, could reduce or prevent the neurological disordersassociated with A

protein.

PCT publication number WO 96/29313 discloses the general formula:

covering metalloprotease inhibiting compounds useful for the treatmentof diseases associated with excess and/or unwanted matrixmetalloprotease activity, particularly collagenase and or stromelysinactivity.

Compounds of general formula:

are disclosed in PCT publication number WO 95/22966 relating to matrixmetalloprotease inhibitors. The compounds of the invention are usefulfor the treatment of conditions associated with the destruction ofcartilage, including corneal ulceration, osteoporosis, periodontitis andcancer. European Patent Application number EP 0652009A1 relates to thegeneral formula:

and discloses compounds that are protease inhibitors that inhibit Aβproduction. U.S. Pat. No. 5,703,129 discloses the general formula:

which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives thatinhibit Aβ production and are useful in the treatment of Alzheimer'sdisease.

Copending, commonly assigned U.S. patent application Ser. No. 09/370,089filed Aug. 7, 1999 (equivalent to international application PCTUS99/17717) discloses lactams of general formula:

wherein the lactam ring B is substituted by succinimide and acarbocyclic, aryl, or heteroaryl group. These compounds inhibit theprocessing of amyloid precursor protein and, more specifically, inhibitthe production of Aβ-peptide, thereby acting to prevent the formation ofneurological deposits of amyloid protein.

None of the above references teaches or suggests the compounds of thepresent invention which are described in detail below.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds whichare useful as inhibitors of the production of Aβ protein orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating degenerative neurological disorders comprising administering toa host in need of such treatment a therapeutically effective amount ofat least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of Formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein Q,R⁵, R⁶, W, X, Y, Z, and ring B are defined below, are effectiveinhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novelcompound of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   Q is —(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—R⁴,    -   —(CR⁷R^(7a))_(n)—O—R⁴,    -   —(CR⁷R^(7a))_(m)—N(R^(7b))—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)₂—R⁴, or    -   —(CR⁷R^(7a))_(n)—C(═O)—R⁴;    -   provided when n is 0, then R⁴ is not H;-   m is 1, 2, or 3;-   n is 0, 1, or 2;-   R⁴ is H,    -   C₁-C₈ alkyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, Cl,    F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, OR^(14a), OR²², SR²², C(═O)OR²²,    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from: H, C₁-C₆    alkyl, CF₃, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁶ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(6a);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(6b); or    -   C₆-C₁₀ aryl substituted with 0-3 R^(6b);-   R^(6a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, aryl or CF₃;-   R^(6b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R⁷, at each occurrence, is independently H or C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently H or C₁-C₄ alkyl;-   R^(7b) is H or C₁-C₄ alkyl;-   Ring B is a 7 membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹⁰)—;-   additionally, two R¹¹ substituents on adjacent atoms may be combined    to form a benzo fused radical; wherein said benzo fused radical is    substituted with 0-4 R¹³;-   additionally, two R¹¹ substituents on adjacent atoms may be combined    to form a 5 to 6 membered heteroaryl fused radical, wherein said 5    to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms    selected from N, O, and S; wherein said 5 to 6 membered heteroaryl    fused radical is substituted with 0-3 R¹³;-   additionally, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle substituted with    0-3 R¹³;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl optionally substituted with 0-3 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,    -   C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   W is a bond or —(CR⁸R^(8a))_(p)—;-   p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or    —OC(═O)—;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,    S(═O)CH₃, S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, aryl, C₃-C₆ cycloalkyl,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆    cycloalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, R¹⁵ and R¹⁶, together with the nitrogen to which they    are attached, may combine to form a 4-7 membered ring wherein said    4-7 membered ring optionally contains an additional heteroatom    selected from O or NH;-   R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or —CH₂-aryl substituted by 0-4 R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃,    SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R^(19b), at each occurrence, is independently is H or C₁-C₄ alkyl;-   R²¹ is H, phenyl, benzyl, or C₁-C₄ alkyl; and-   R²² is C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₃-C₄ alkynyl.

In a preferred embodiment, the present invention provides for a compoundof Formula (I), or a pharmaceutically acceptable salt or prodrugthereof, wherein:

-   Q is —(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—R⁴,    -   —(CR⁷R^(7a))_(n)—O—R⁴, or    -   —(CR⁷R^(7a))_(m)—N(R^(7b))—R⁴;-   m is 1 or 2;-   n is 0 or 1;-   R⁴ is H,    -   C₁-C₈ alkyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, Cl,    F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, OR^(14a), C(═O)OR²², SR²², OR²²,    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from: H, C₁-C₆    alkyl, CF₃, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁶ is H, methyl, or ethyl;-   R⁷, at each occurrence, is independently H or C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently H or C₁-C₄ alkyl;-   R^(7b) is H or C₁-C₄ alkyl;-   Ring B is selected from-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl optionally substituted with 0-3 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 hetero atoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,    C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   W is a bond or —(CH₂)_(p)—;-   p is 1 or 2;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ carbocycle substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃    haloalkoxy, and C₁-C₃ halothioalkoxy;-   Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or    —OC(═O)—;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,    S(═O)CH₃, S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆    cycloalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, R¹⁵ and R¹⁶, together with the nitrogen to which they    are attached, may combine to form a 4-7 membered ring wherein said    4-7 membered ring optionally contains an additional heteroatom    selected from O or NH;-   R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or —CH₂-aryl substituted by 0-4 R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃,    SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;-   R^(19b), at each occurrence, is independently is H or C₁-C₄ alkyl;-   R²¹ is H, phenyl, benzyl, or C₁-C₄ alkyl; and-   R²² is C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₃-C₄ alkynyl.

In another preferred embodiment, the present invention provides for acompound of Formula (Ib),

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   Q is —(CHR⁷)_(m)—R⁴,    -   —(CHR⁷)_(n)—S—R⁴,    -   —(CHR⁷)_(n)—O—R⁴, or    -   —(CHR⁷)_(m)—N(R^(7b))—R⁴;-   m is 1 or 2;-   n is 0 or 1;-   R⁴ is H,    -   C₁-C₈ alkyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, Cl,    F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, OR^(14a), C(═O)OR²², SR²², OR²²,    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from: H, C₁-C₆    alkyl, CF₃, Cl, F, Br, I, ═O, CN, NO₂, R¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁷, at each occurrence, is independently H, methyl, or ethyl;-   R^(7b) is H, methyl, or ethyl;-   Ring B is selected from-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,    C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   W is a bond;-   X is a bond;-   Y is a bond;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,    S(═O)CH₃, S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆    cycloalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;    -   alternatively, R¹⁵ and R¹⁶, together with the nitrogen to which        they are attached, may combine to form a 4-7 membered ring        wherein said 4-7 membered ring optionally contains an additional        heteroatom selected from O or NH;-   R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or —CH₂-aryl substituted by 0-4 R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃,    SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;-   R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and-   R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, and    propargyl.

In another preferred embodiment, the present invention provides for acompound of Formula (1), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —(CH₂)_(m)—R⁴,    -   —(CH₂)_(n)—S—R⁴,    -   —(CH₂)_(n)—O—R⁴, or    -   —(CH₂)_(m)—N(H)—R⁴;-   m is 1 or 2;-   n is 0 or 1;-   R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, Cl,    F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR²², OR^(14a),    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from: H, C₁-C₆    alkyl, CF₃, Cl, F, Br, I, ═O, CN, NO₂, R¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and    -   C₁-C₄ haloalkoxy;-   Ring B is selected from:-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); and    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   W is a bond;-   X is a bond;-   Y is a bond;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-3 R^(12a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(12a); or    -   C₂-C₆ alkynyl substituted with 0-3 R^(12a);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,    S(═O)CH₃, S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b); and        wherein said 5 to 10 membered heterocycle is selected from        pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,        pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,        tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,        benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,        benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,        quinolinyl, and isoquinolinyl;-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆    cycloalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄    alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄    alkyl)-S(═O)₂—; and-   alternatively, R¹⁵ and R¹⁶, together with the nitrogen to which they    are attached, may combine to form a 4-6 membered ring wherein said    4-6 membered ring optionally contains an additional heteroatom    selected from O or NH, wherein said 4-6 membered ring is selected    from imidazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl,    morpholinyl, and thiomorpholinyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;-   R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and-   R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, and    propargyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴;-   R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₆ carbocycle substituted with 0-3 R^(4b), phenyl substituted        with 0-3 R^(4b), or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from H, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR^(14a), OR²²,    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R_(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b); or    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);-   R^(5b), at each occurrence, is independently selected from: H,    methyl, ethyl, propyl, butyl, CF₃, Cl, F, Br, I, ═O;    -   C₃-C₆ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    -   C₁-C₂ haloalkoxy;-   Ring B is selected from-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); and    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F,    Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   W is a bond;-   X is a bond;-   Y is a bond;-   Z is H;    -   C₁-C₄ alkyl substituted with 0-3 R^(12a);    -   C₂-C₄ alkenyl substituted with 0-3 R^(12a); or    -   C₂-C₄ alkynyl substituted with 0-3 R^(12a);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄    alkyl, and benzyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—,    ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁹, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl;-   R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and-   R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, and    propargyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴;-   R⁴ is C₁-C₆ alkyl substituted with 0-2 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-2 R^(4a), or    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, OH,    F, Cl, Br, I, CN, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, methoxy,    ethoxy, propoxy, OCF₃;    -   C₃-C₆ carbocycle substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(4b); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;    -   R^(4b), at each occurrence, is independently selected from H,        OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₄ alkyl substituted with 0-1 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-1 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-1 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃;    -   C₃-C₆ carbocycle substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(5c); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃,    -   C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂        haloalkoxy;-   Ring B is selected from:    R¹¹, at each occurrence, is independently selected from    -   H, ═O, NR¹⁸R¹⁹;    -   C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O,    NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   W is a bond;-   X is a bond;-   Y is a bond;-   Z is H;    -   C₁-C₄ alkyl substituted with 0-1 R^(12a);    -   C₂-C₄ alkenyl substituted with 0-1 R^(12a); or    -   C₂-C₄ alkynyl substituted with 0-1 R^(12a);-   R^(12a), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹³, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN,    NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl; and-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, benzyl, and phenethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Ring B is selected from    R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂N(CH₃)₂,    —CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂N(CH₂CH₃)₂,    —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,    —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,    —CH₂CH₂-cyclopentyl, or —CH₂CH₂-cyclohexyl;-   Q is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH(CH₃)₂,    —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,    —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,    —CH₂CH₂-cyclopentyl, —CH₂CH₂-cyclohexyl, —OCH₃, —OCH₂CH₃,    —OCH₂CH₂CH₃, —OCH(CH₃)₂, —OCH₂CH₂CH₂CH₃, —OCH₂CH(CH₃)₂,    —OCH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₂CH₂CH₃,    —OCH₂CH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH(CH₃)₂, —OCH₂-cyclopropyl,    —OCH₂-cyclobutyl, —OCH₂-cyclopentyl, —OCH₂-cyclohexyl,    —OCH₂CH₂-cyclopropyl, —OCH₂CH₂-cyclobutyl, —OCH₂CH₂-cyclopentyl,    —OCH₂CH₂-cyclohexyl, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂—OCH(CH₃)₂,    —CH₂OCH₂CH₂CH₂CH₃, —CH₂OCH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₂CH₃,    —CH₂OCH₂CH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH(CH₃)₂, —CH₂O-cyclopropyl,    —CH₂O-cyclobutyl, —CH₂O-cyclopentyl, —CH₂O-cyclohexyl,    —CH₂OCH₂-cyclopropyl, —CH₂OCH₂-cyclobutyl, —CH₂OCH₂-cyclopentyl,    —CH₂OCH₂-cyclohexyl; —CH₂(NH)CH₃, —CH₂(NH)CH₂CH₃, —CH₂(NH)CH₂CH₂CH₃,    —CH₂—(NH)CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH(CH₃)₂,    —CH₂(NH)CH₂CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH₂CH(CH₃)₂,    —CH₂(NH)CH₂CH₂CH₂CH(CH₃)₂, —CH₂(NH)-cyclopropyl,    —CH₂(NH)-cyclobutyl, —CH₂(NH)-cyclopentyl, —CH₂(NH)-cyclohexyl,    —CH₂(NH)CH₂-cyclopropyl, —CH₂(NH)CH₂-cyclobutyl,    —CH₂(NH)CH₂-cyclopentyl, or —CH₂(NH)CH₂-cyclohexyl;-   W is a bond;-   X is a bond;-   Y is a bond;-   Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl,    t-butyl, or allyl;-   R¹¹, at each occurrence, is independently selected from H, ═O,    methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—,    (3-F-phenyl)CH₂CH₂—, 2-F-phenyl, (2-F-phenyl)CH₂—,    (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—,    (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—,    (3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,    (4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—,    (3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—,    (4-CF₃-phenyl)CH₂CH₂—, pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl,    4-CH₃-pyrid-2-yl, 4-CF₃-pyrid-2-yl, pyrid-3-yl, 4-F-pyrid-3-yl,    4-Cl-pyrid-3-yl, 4-CH₃-pyrid-3-yl, 4-CF₃-pyrid-3-yl, or pyrid-4-yl;    and-   R¹³, at each occurrence, is independently selected from H, F, Cl,    OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —(CH₂)_(m)—R⁴,    -   —(CH₂)_(n)—S—R⁴,    -   —(CH₂)_(n)—O—R⁴, or    -   —(CH₂)_(m)—N(H)—R⁴;-   m is 1 or 2;-   n is 0 or 1;-   R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₈ alkynyl-substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, Cl,    F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR²², OR^(14a),    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from: H, C₁-C₆    alkyl, CF₃, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and    -   C₁-C₄ haloalkoxy;-   Ring B is selected from    R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl optionally substituted with 0-3 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); and        wherein said 5 to 6 membered heterocycle is selected from        pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,        pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,        oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted    with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and    -   C₁-C₄ haloalkoxy;-   W is a bond, —CH₂—, —CH₂CH₂—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or    —OC(═O)—;-   Z is C₁-C₃ alkyl substituted with 1-2 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and    -   C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆    cycloalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄    alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄    alkyl)-S(═O)₂—; and-   alternatively, R¹⁵ and R¹⁶, together with the nitrogen to which they    are attached, may combine to form a 4-6 membered ring wherein said    4-6 membered ring optionally contains an additional heteroatom    selected from O or NH, wherein said 4-6 membered ring is selected    from imidazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl,    morpholinyl, and thiomorpholinyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and-   R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, and    propargyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —CH₂R⁴, —O—R⁴, or —CH²—NH—R⁴;-   R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(4a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(4a);    -   C₃-C₆ carbocycle substituted with 0-3 R^(4b);    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from H, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR^(14a), OR²²,    NR²¹R²², S(═O)R²², S(═O)₂R²²,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b); or    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, Cl, F, Br, I, ═O;    -   C₃-C₆ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    -   C₁-C₂ haloalkoxy;-   Ring B is selected from-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl optionally substituted with 0-3 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); and        wherein said 5 to 6 membered heterocycle is selected from        pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,        pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,        oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, Cl,    F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and    -   C₁-C₄ haloalkoxy;-   W is a bond, —CH₂—, —CH₂CH₂—;-   X is a bond;    -   phenyl substituted with 0-1 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-1 R^(Xb);-   R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,    S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy, ethoxy,    propoxy, and —OCF₃;-   Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—;-   Z is C₁-C₂ alkyl substituted with 1-2 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄    alkyl, and benzyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—,    ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁹, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl; and-   R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and-   R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, and    propargyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴;-   R⁴ is C₁-C₆ alkyl substituted with 0-2 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-2 R^(4a), or    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, OH,    F, Cl, Br, I, CN, NR₁₅NR₁₆, CF₃, methyl, ethyl, propyl, butyl,    methoxy, ethoxy, propoxy, OCF₃;    -   C₃-C₆ carbocycle substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(4b); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃,    -   C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    -   C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁵ is H;    -   C₁-C₄ alkyl substituted with 0-1 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-1 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-1 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃;    -   C₃-C₆ carbocycle substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(5c); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,        isoxazolyl, and tetrazolyl;-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   Ring B is selected from:-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹;    -   C₁-C₄ alkyl optionally substituted with 0-3 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(11b); and        wherein said 5 to 6 membered heterocycle is selected from        pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,        pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,        oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, Cl,    F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   W is a bond or —CH₂—;-   X is a bond;    -   phenyl substituted with 0-1 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-1 R^(Xb);-   R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, methyl,    ethyl, methoxy, ethoxy, and —OCF₃;-   Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—;-   Z is C₁-C₂ alkyl substituted with 1-2 R^(12a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12a), at each occurrence, is independently selected from    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b); and        wherein said 5 to 10 membered heterocycle is selected from        pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,        pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,        tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,        benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,        benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,        quinolinyl, and isoquinolinyl;-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and —OCF₃;-   R¹³, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN,    NR¹⁵R¹⁶, and CF₃;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl; and-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, benzyl, and phenethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl.

In another preferred embodiment, the present invention provides for acompound of Formula (I), or a pharmaceutically acceptable salt orprodrug thereof, wherein:

-   Ring B is selected from    R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂N(CH₃)₂,    —CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂N(CH₂CH₃)₂,    —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,    —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,    —CH₂CH₂-cyclopentyl, or —CH₂CH₂-cyclohexyl;-   Q is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH(CH₃)₂,    —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,    —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,    —CH₂CH₂-cyclopentyl, —CH₂CH₂-cyclohexyl, —OCH₃, —OCH₂CH₃,    —OCH₂CH₂CH₃, —OCH(CH₃)₂, —OCH₂CH₂CH₂CH₃, —OCH₂CH(CH₃)₂,    —OCH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₂CH₂CH₃,    —OCH₂CH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH(CH₃)₂, —OCH₂-cyclopropyl,    —OCH₂-cyclobutyl, —OCH₂-cyclopentyl, —OCH₂-cyclohexyl,    —OCH₂CH₂-cyclopropyl, —OCH₂CH₂-cyclobutyl, —OCH₂CH₂-cyclopentyl,    —OCH₂CH₂-cyclohexyl, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂—OCH(CH₃)₂,    —CH₂OCH₂CH₂CH₂CH₃, —CH₂OCH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₂CH₃,    —CH₂OCH₂CH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH(CH₃)₂, —CH₂O-cyclopropyl,    —CH₂O-cyclobutyl, —CH₂O-cyclopentyl, —CH₂O-cyclohexyl,    —CH₂OCH₂-cyclopropyl, —CH₂OCH₂-cyclobutyl, —CH₂OCH₂-cyclopentyl,    —CH₂OCH₂-cyclohexyl; —CH₂(NH)CH₃, —CH₂(NH)CH₂CH₃, —CH₂(NH)CH₂CH₂CH₃,    —CH₂—(NH)CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH(CH₃)₂,    —CH₂(NH)CH₂CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH₂CH(CH₃)₂,    —CH₂(NH)CH₂CH₂CH₂CH(CH₃)₂, —CH₂(NH)-cyclopropyl,    —CH₂(NH)-cyclobutyl, —CH₂(NH)-cyclopentyl, —CH₂(NH)-cyclohexyl,    —CH₂(NH)CH₂-cyclopropyl, —CH₂(NH)CH₂-cyclobutyl,    —CH₂(NH)CH₂-cyclopentyl, or —CH₂(NH)CH₂-cyclohexyl;-   W is a bond or —CH₂—;-   X is a bond;-   Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or    —N(CH₃)—,-   Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,    3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,    2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,    2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,    3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,    3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,    2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,    4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,    thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,    1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,    phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,    (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—,    (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,    (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,    (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,    (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,    (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,    (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,    (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,    (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,    (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,    (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,    (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,    (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,    (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,    (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—, or    (phenyl)₂CH—;-   R¹¹, at each occurrence, is independently selected from H, ═O,    methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—,    (3-F-phenyl)CH₂CH₂—, 2-F-phenyl, (2-F-phenyl)CH₂—,    (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—,    (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—,    (3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,    (4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—,    (3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—,    (4-CF₃-phenyl)CH₂CH₂—, pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl,    4-CH₃-pyrid-2-yl, 4-CF₃-pyrid-2-yl, pyrid-3-yl, 4-F-pyrid-3-yl,    4-Cl-pyrid-3-yl, 4-CH₃-pyrid-3-yl, 4-CF₃-pyrid-3-yl, or pyrid-4-yl;    and-   R¹³, at each occurrence, is independently selected from H, F, Cl,    OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.

In another preferred embodiment, the present invention provides for acompound of Formula (Ic):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the present invention provides for acompound of Formula (Id):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the present invention provides for acompound of Formula (Ie):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the present invention provides for acompound of Formula (If):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the present invention provides for acompound, or a pharmaceutically acceptable salt or prodrug thereof,selected from:

-   (3S)-3-[(1-oxo-(2S)-2-cyclopropylmethyl-heptyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-propyloctyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-propylnonanyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-butyloctyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-(1-oxo-2-methyloctyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-pentylheptanyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-propylpentyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (3S)-3-[(1-oxo-2-methylpentyl)amino]-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one;-   3-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-[4-methyl(pyridin-2-yl)]-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-[4-trifluoromethyl(pyridin-2-yl)]-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-[1-oxo-2-(S)-aminomethyl-heptyl]amino-1-methyl-(5-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one;-   3-[1-oxo-2-(S)-(dimethylamino)methyl-heptyl]amino-1-methyl-5-(trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one;    and-   3-(3-isopentyloxy-2-(R)-methyl-1-oxo-propyl)amino-1-methyl-5-(trifluoromethyl)phneyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.

In another preferred embodiment, the present invention provides for acompound, or a pharmaceutically acceptable salt or prodrug thereof,selected from:

-   (7S)-[(2S)-1-oxo-2-pentyloxy-4-methylpentyl]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one.

It is appreciated that certain features of the invention, which are, forclarity, described herein in the context of separate embodiments, mayalso be provided in combination in a single embodiment. As such, it isunderstood that any and all embodiments of the present invention may betaken in conjunction with any other embodiment to describe additionalembodiments of the present invention. Conversely, various features ofthe invention which are for brevity, described herein in the context ofa single embodiment, may also be provided separately or in anysubcombination. As such, it is understood that any elements of anembodiment are meant to be combined with any and all other elements fromany of the embodiments to describe additional embodiments.

In a preferred embodiment Ring B is selected from:

In another preferred embodiment Ring B is selected from:

In another preferred embodiment Ring B is singly:

In another preferred embodiment Ring B is singly:

Also included in the present invention are compounds as set forth in theembodiments above wherein Q is —(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—S—R⁴, —(CR⁷R^(7a))_(n)—O—R⁴, or—(CR⁷R^(7a))_(m)—N(R^(7b))—R⁴.

In a preferred embodiment Q is —(CHR⁷)_(m)—R⁴, —(CHR⁷)_(n)—S—R⁴,—(CHR⁷)_(n)—O—R⁴, or —(CHR⁷)_(m)—N(R^(7b))—R⁴.

In another preferred embodiment Q is —(CH₂)_(m)—R⁴, —(CH₂)_(n)—S—R⁴,—(CH₂)_(n)—O—R⁴, or —(CH₂)_(m)—N(H)—R⁴.

In another preferred embodiment Q is —(CH₂)_(m)—R⁴, —(CH₂)_(n)—O—R⁴, or—(CH₂)_(m)—N(H)—R⁴.

In another preferred embodiment Q is —CH₂R⁴, —O—R⁴, —CH₂OR⁴, or—CH₂—NH—R⁴.

In another preferred embodiment Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴.

In another preferred embodiment Q is —CH₂R⁴.

In another preferred embodiment Q is —CH₂OR⁴ or —O—R⁴.

In another preferred embodiment Q is —CH₂OR⁴.

In another preferred embodiment Q is —O—R⁴.

In another preferred embodiment Q is —CH₂—NH—R⁴.

In another preferred embodiment Q is —CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂CH₂CH₂CH(CH₃)₂.

In another preferred embodiment Q is —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, or —CH₂CH₂-cyclohexyl.

In another preferred embodiment Q is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)₂, —OCH₂CH₂CH₂CH₃, —OCH₂CH(CH₃)₂, —OCH₂CH₂CH(CH₃)₂,—OCH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH(CH₃)₂, or—OCH₂CH₂CH₂CH₂CH(CH₃)₂.

In another preferred embodiment Q is —OCH₂-cyclopropyl,—OCH₂-cyclobutyl, —OCH₂-cyclopentyl, —OCH₂-cyclohexyl,—OCH₂CH₂-cyclopropyl, —OCH₂CH₂-cyclobutyl, —OCH₂CH₂-cyclopentyl, or—OCH₂CH₂-cyclohexyl.

In another preferred embodiment Q is —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂OCH₂CH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₃, —CH₂OCH₂CH(CH₃)₂,—CH₂OCH₂CH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₂CH₃, —CH₂OCH₂CH₂CH₂CH₂CH₂CH₃,—CH₂OCH₂CH₂CH₂CH(CH₃)₂, or —CH₂OCH₂CH₂CH₂CH₂CH(CH₃)₂.

In another preferred embodiment Q is —CH₂OCH₂-cyclopropyl,CH₂OCH₂-cyclobutyl, CH₂OCH₂-cyclopentyl, CH₂OCH₂-cyclohexyl,CH₂OCH₂CH₂-cyclopropyl, CH₂OCH₂CH₂-cyclobutyl, CH₂OCH₂CH₂-cyclopentyl,or CH₂OCH₂CH₂-cyclohexyl.

It is provided that in the definition of Q, when n is 0 then R⁴ can notbe H.

Also included in the present invention are compounds as set forth in theembodiments above wherein the integer m may be selected from 1, 2, or 3.

In another preferred embodiment the integer m is 1 or 2.

In another preferred embodiment the integer m is 2.

In another preferred embodiment the integer m is 1.

Also included in the present invention are compounds as set forth in theembodiments above wherein the integer n may be selected from 0, 1, or 2;provided that when R⁴ can not be H.

In another preferred embodiment the integer n is 0 or 1.

In another preferred embodiment the integer n is 0.

In another preferred embodiment the integer n is 1.

In another preferred embodiment the integer n is 2.

Also included in the present invention are compounds as set forth in theembodiments above wherein R⁴ is H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, or C₃-C₁₀ carbocycle.

In another preferred embodiment R⁴ is C₂-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, or C₃-C₆ cycloaklyl.

In another preferred embodiment R⁴ is C₃-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, or C₃-C₆ cycloaklyl.

In another preferred embodiment R⁴ is C₄-C₈ alkyl, C₄-C₈ alkenyl, C₄-C₈alkynyl, or C₃-C₆ cycloaklyl.

In another preferred embodiment R⁴ is C₂-C₈ alkyl.

In another preferred embodiment R⁴ is C₃-C₈ alkyl.

In another preferred embodiment R⁴ is C₄-C₈ alkyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein R⁵ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, or (C₃-C₆ cycloalkyl)C₁-C₄ alkyl, (NR¹⁵R¹⁶)C₁-C₄ alkyl.

In another preferred embodiment R⁵ is C₂-C₈ alkyl, C₂-C₈ alkenyl, orC₂-C₈ alkynyl.

In another preferred embodiment R⁵ is C₃-C₈ alkyl, C₃-C₈ alkenyl, orC₃-C₈ alkynyl.

In another preferred embodiment R⁵ is C₄-C₈ alkyl, C₄-C₈ alkenyl, C₄-C₈alkynyl.

In another preferred embodiment R⁵ is C₂-C₈ alkyl.

In another preferred embodiment R⁵ is C₃-C₈ alkyl.

In another preferred embodiment R⁵ is C₄-C₈ alkyl.

In another preferred embodiment R⁵ is (C₃-C₆ cycloalkyl)C₁-C₄ alkyl.

In another preferred embodiment R⁵ is (NR¹⁵R¹⁶)C₁-C₄ alkyl.

In another preferred embodiment R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NH₂,—CH₂N(CH₃)₂, —CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂,—CH₂CH₂N(CH₂CH₃)₂, —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl,or —CH₂-cyclohexyl.

In another preferred embodiment R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH(CH₃)₂, or —CH₂CH₂CH₂CH₂CH(CH₃)₂.

In another preferred embodiment R⁵ is —CH₂NH₂, —CH₂N(CH₃)₂,—CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, or —CH₂CH₂N(CH₂CH₃)₂.

In another preferred embodiment R⁵ is —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, or —CH₂-cyclohexyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein R⁶ is H.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹¹ is H, NR¹⁸R¹⁹;

-   -   C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); or    -   pyridinyl substituted with 0-3 R^(11b);    -   wherein R^(11a) is phenyl substituted with 0-3 R^(11b);    -   wherein R^(11b), at each occurrence, is independently selected        from H, OH, Cl, F, CF₃, methyl, ethyl, propyl, butyl, methoxy,        ethoxy, and propoxy.

In another preferred embodiment R¹¹ is independently selected from H,methyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—,(4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—,2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,(4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—,(3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,(4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—,(3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—,(4-CF₃-phenyl)CH₂CH₂—, pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl,4-CH₃-pyrid-2-yl, 4-CF₃-pyrid-2-yl, pyrid-3-yl, 4-F-pyrid-3-yl,4-Cl-pyrid-3-yl, 4-CH₃-pyrid-3-yl, 4-CF₃-pyrid-3-yl, and pyrid-4-yl.

In another preferred embodiment R¹¹ is independently selected from H,methyl, phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 4-Cl-phenyl,3-Cl-phenyl, 4-CH₃-phenyl, 3-CH₃-phenyl, 4-CF₃-phenyl, pyrid-2-yl,4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 4-CH₃-pyrid-2-yl, and 4-CF₃-pyrid-2-yl.

Also included in the present invention are compounds as set forth in theembodiments above wherein W may be selected from a bond, —CH₂—,—CH₂CH₂—, or —CH(CH₃)—.

In another preferred embodiment W is a bond or —(CH₂)_(p)—.

In another preferred embodiment W is a bond, —CH₂—, or —CH₂CH₂—.

In another preferred embodiment W is a bond or —CH₂—.

In another preferred embodiment W is —CH₂—.

In another preferred embodiment W is a bond.

Also included in the present invention are compounds as set forth in theembodiments above wherein the integer p may be selected from 0, 1, 2, or3.

In another preferred embodiment the integer p is 0, 1 or 2.

In another preferred embodiment the integer p is 0 or 1.

In another preferred embodiment the integer p is 0.

Also included in the present invention are compounds as set forth in theembodiments above wherein X is a bond, C₆-C₁₀ aryl, C₃-C₁₀ carbocycle or5 to 10 membered heterocycle.

In another preferred embodiment X is a bond, phenyl, C₃-C₆ carbocycle,or 5 or 6 membered heterocycle.

In another preferred embodiment X is a bond, phenyl, C₃-C₆ cycoalkyl, or5 or 6 membered heterocycle.

In another preferred embodiment X is a bond;

In another preferred embodiment X is a bond;

In another preferred embodiment X is a bond or phen-1,3-diyl.

In another preferred embodiment X is phen-1,3-diyl.

In another preferred embodiment X is a bond.

Also included in the present invention are compounds as set forth in theembodiments above wherein Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,—S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or—OC(═O)—.

In another preferred embodiment Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —N(CH₃)—, —C(═O)NH—, —NHC(═O)—, —NHS(═O)₂—, —S(═O)₂NH—,—NHS(═O)—, —S(═O)NH—, —C(═O)O—, or —OC(═O)—.

In another preferred embodiment Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—.

In another preferred embodiment Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, or —N(CH₃)—.

In another preferred embodiment Y is a bond, —C(═O)—, —O—, —NH—, or—N(CH₃)—.

In another preferred embodiment Y is —O—.

In another preferred embodiment Y is —NH—.

In another preferred embodiment Y is —N(CH₃)—.

In another preferred embodiment Y is a bond.

Also included in the present invention are compounds as set forth in theembodiments above wherein Z is

-   -   C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,    -   C₁-C₂ alkyl substituted with 1-2 R^(12a);    -   phenyl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);    -   wherein R^(12a) is phenyl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b); and    -   wherein R^(12b), at each occurrence, is independently selected        from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,        propoxy, and —OCF₃;

In another preferred embodiment Z is

-   -   C₁-C₂ alkyl substituted with 1-2 R^(12a); or    -   phenyl substituted with 0-4 R^(12b);    -   wherein R^(12a) is phenyl substituted with 0-4 R^(12b);    -   wherein R^(12b), at each occurrence, is independently selected        from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,        propoxy, and —OCF₃;

In another preferred embodiment Z is C₁-C₄ alkyl, C₂-C₄ alkenyl, orC₂-C₄ alkynyl.

In another preferred embodiment Z is phenyl, 2-F-phenyl, 3-F-phenyl,4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl,3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl,4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl,3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl,furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,(2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—,(2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,(2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,(2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,(2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,(3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,(2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,(2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,(2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,(2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,(furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,(3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,(oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,(cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,(cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—, or (phenyl)₂CH—.

In another preferred embodiment Z is phenyl, 2-F-phenyl, 3-F-phenyl,4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl,3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl,4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl,3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl,or 4-phenyl-phenyl.

In another preferred embodiment Z is phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, or (phenyl)₂CH—.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹³, at each occurrence, is independentlyselected from H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, and —CF₃.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹⁴ is H, phenyl, benzyl, methyl, ethyl,propyl, or butyl;

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹⁵, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, and butyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹⁶, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, benzyl, andphenethyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹⁸, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein R¹⁹, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, and butyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein in the moiety R⁴—(CR⁷R^(7a))m-(R⁵)CH— ofFormula (I) when R⁴ is an alkyl, alkenyl, or alkynyl moiety; and R⁵ isan alkyl, alkenyl, or alkynyl moiety; then the total number of carbonatoms in the backbone of R⁴—(CR⁷R^(7a))m-(R⁵)CH— equals nine or more.

For example, when R⁵ is methyl, then R⁴—(CR⁷R^(7a))m- is heptyl(branched or linear) or greater. For example, when R⁵ is ethyl, thenR⁴—(CR⁷R^(7a))m- is hexyl (branched or linear) or greater. It isunderstood that the proviso is only intended to define the number ofcarbon atoms, continuously linked in the backbone of theR⁴—(CR⁷R^(7a))m-(R⁵)CH— moiety and not meant to limit substitution byR^(4a) or R^(5b) on the R⁴—(CR⁷R^(7a))m-(R⁵)CH—.

Also included in the present invention are compounds as set forth in theembodiments above wherein in the moiety R⁴—O(CR⁷R^(7a))n-(R⁵)CH— ofFormula (I) when —(CR⁷R^(7a))n-(R⁵)CH— is C₁-C₈ alkyl, C₂-C₈ alkenyl,C₃-C₁₀ cycloalkyl-C₁-C₄ alkyl, C₆-C₁₀ aryl-C₁-C₄ alkyl, C₆-C₁₀aryl-C₂-C₄ alkynyl, then R⁴ is other than H, methyl, ethyl, isopropyl,phenyl, or benzyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein in the moiety R⁴—O(CR⁷R^(7a))n-(R⁵)CH— ofFormula (I) when —(CR⁷R^(7a))n-(R⁵)CH— is C₁-C₄ alkyl, then R⁴ is otherthan C₁-C₄ alkyl.

Also included in the present invention are compounds as set forth in theembodiments above wherein in the moiety R⁴—NR^(7b)(CR⁷R^(7a))n-(R⁵)CH—of Formula (I) when —(CR⁷R^(7a))n-(R⁵)CH— is C₂-C₄ alkyl, then R⁴ isother than C₂-C₄ alkyl.

In a second embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In a third embodiment, the present invention provides a method for thetreatment of neurological disorders associated with β-amyloid productioncomprising administering to a host in need of such treatment atherapeutically effective amount of a compound of Formula (I).

In a preferred embodiment the neurological disorder associated withβ-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method forinhibiting γ-secretase activity for the treatment of a physiologicaldisorder associated with inhibiting γ-secretase activity comprisingadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of Formula (I) that inhibits γ-secretaseactivity.

Thus, the present invention provides a method for inhibiting γ-secretaseactivity comprising administering to a host in need of such inhibition atherapeutically effective amount of a compound of Formula (I) thatinhibits γ-secretase activity.

In a preferred embodiment the physiological disorder associated withinhibiting γ-secretase activity is Alzheimer's Disease.

In a fifth embodiment, the present invention provides a compound ofFormula (I) for use in therapy.

In a preferred embodiment the present invention provides a compound ofFormula (I) for use in therapy of Alzheimer's Disease.

In a sixth embodiment, the present invention provides for the use of acompound of Formula (I) for the manufacture of a medicament for thetreatment of Alzheimer's Disease.

Definitions

As used herein, the term “Aβ” denotes the protein designated Aβ,β-amyloid peptide, and sometimes β/A4, in the art. Aβ is anapproximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acidsfound in amyloid plaques, the walls of meningeal and parenchymalarterioles, small arteries, capillaries, and sometimes, venules. Theisolation and sequence data for the first 28 amino acids are describedin U.S. Pat. No. 4,666,829. The 43 amino acid sequence is: 1 Asp Ala GluPhe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met ValGly Gly Val Val 41 Ile Ala Thr

The term “APP”, as used herein, refers to the protein known in the artas β precursor protein. This protein is the precursor for Aβ and throughthe activity of “secretase” enzymes, as used herein, it is processedinto Aβ. Differing secretase enzymes, known in the art, have beendesignated β secretase, generating the N-terminus of Aβ, α secretasecleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, asused herein, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(5b)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-3 R^(5b), thensaid group may optionally be substituted with up to three R^(5b) groupsand R^(5b) at each occurrence is selected independently from thedefinition of R^(5b). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred“alkyl” group, unless otherwise specified, is “C₁-C₄ alkyl”.Additionally, unless otherwise specified, “propyl” denotes n-propyl ori-propyl; “butyl” denotes n-butyl, i-butyl, sec-butyl, or t-butyl.

As used herein, “alkenyl” or “alkenylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain. Examples of “C₂-C₆ alkenyl” include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl,hexenyl, and the like.

As used herein, “alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more carbon-carbon triple bonds which may occur in any stablepoint along the chain, such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, ands-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or“thioalkoxy” is represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo. Unless otherwise specified, preferred halo is fluoro and chloro.“Counterion” is used to represent a small, negatively charged speciessuch as chloride, bromide, hydroxide, acetate, sulfate, and the like.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(V)F_(W) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl.“Haloalkoxy” is intended to mean a haloalkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge;for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy,and the like. “Halothioalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and 1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocyclesinclude, but are not limited to, pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, butare not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring andspiro compounds containing, for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromatic residue, isintended to mean an aromatic moiety containing the specified number ofcarbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred“aryl” is phenyl. Unless otherwise specified, “aryl” may beunsubstituted or substituted with 0 to 3 groups selected from H, methyl,ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy,Cl, F, Br, I, CF₃, SCH₃, S(O)CH₃, SO₂CH₃, —N(CH₃)₂, N(CH₃)H, CN, NO₂,OCF₃, C(═O)CH₃, CO₂H, CO₂CH₃, or C₁-C₄ haloalkyl.

As used herein, the term “heteroaryl fused radical” is intended todenote a 5 or 6 membered aromatic ring comprising carbon atoms and oneor two heteroatoms selected from nitrogen, sulphur and oxygen. The 5 or6 membered ring is fused to two adjacent atoms of a second ring, i.e.forming a bicyclic ring system, wherein the second ring is lactam ringB. Examples of a “heteroaryl fused radical” are furanyl, imidazolyl,isoxazolyl, oxazolyl, pyrrolyl, thiophenyl, thiazolyl, isothiozalyl,pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

The phrase “additional lactam carbons”, as used herein, is intended todenote the number of optional carbon atoms in the lactam ring B ofFormula (I). Formula (I″):

represents the lactam ring B of Formula (I). Additional lactam carbonsare carbons in lactam ring B other than the carbons numbered 2 and 3 inthe backbone of the formula. The additional lactam carbons may beoptionally replaced by a heteroatom selected from oxygen, nitrogen andsulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons,wherein one optional carbon may optionally be replaced by a heteroatom,such that the total number of members of lactam ring B, including atomsnumbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferredthat the total number of atoms of lactam ring B is 6, 7 or 8; it is morepreferred that the total number of atoms of lactam ring B is seven. Itis further understood that lactam ring B may optionally be unsaturatedor partially unsaturated (i.e. two adjacent atoms in the ring form adouble bond) wherein the backbone of lactam ring B may contain one, twoor three double bonds. Examples of lactam ring B include:

but are not intended to limit the invention. Preferred examples oflactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferredexamples of lactam ring B are B1, B6, B8, B9, and B13. Preferredexamples of substituent R¹⁰ or R¹¹ on lactam B are hydrogen, methyl,ethyl, phenyl, benzyl, phenethyl, 4-fluorophenyl, 4-chlorophenyl,4-methylphenyl, 4-CF₃-phenyl, (4-fluorophenyl)methyl,(4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-CF₃-phenyl)methyl,(4-fluorophenyl)ethyl, (4-chlorophenyl)ethyl, (4-methylphenyl)ethyl,(4-CF₃-phenyl)ethyl, and 2-, 3-, and 4-pyridinyl. More preferredexamples of substituent R¹⁰ or R¹¹ on lactam B are methyl, ethyl,phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-CF₃-phenyl,(4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-CF₃-phenyl)methyl,and 2-, 3-, and 4-pyridinyl. Preferred examples of R¹³ on lactam B areF, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.

The compounds herein described may have asymmetric centers. Oneenantiomer of a compound of Formula (I) may display superior biologicalactivity over the opposite enantiomer. For example carbon 3 of lactamring B Formula (I″) may exist in either an S or R configuration. Thus,an R or S configuration at carbon 3 in Formula (I″-3R) and (I″-3S) areconsidered part of the invention. Examples of such configurationinclude,

but are not intended to be limited to this example of ring B. Whenrequired, separation of the racemic material can be achieved by methodsknown in the art. Additionally when the carbon atom to which Q and R⁵are attached is chiral, both the R and S configurations of the carbonatom are considered part of the invention.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and acetamide,formamide, and benzamide derivatives of amine functional groups in thecompounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Compounds of Formula (I) of the present invention can be synthesized bythe method of Scheme 1 comprising: step 1, an amino acid coupling;followed by step 2, a radical reduction; and an optional step 3, areaction with R⁶-LG where LG is a leaving group, for example halide,mesylate, triflate or other leaving group well known to one skilled inthe art. See Scheme 1. In the method of Scheme 1, step 1, aW—X—Y-Z-substituted aminolactam, XI, is coupled with an β-hydroxy acid Xto form a lactam XII. The amine XI is coupled to an appropriatelysubstituted carboxylic acid or acid chloride by methods well describedin the literature for making amide bonds, for example, TBTU in DMF witha base, for example, NMM to give the elaborated compound XII. In step 2,the lactam XII is then reacted with thiocarbonyl diimidazole to form acarbonyl derivative XIII which is then converted to a compound ofFormula (Ia′) by a radical hydride reduction. The deoxygenation oflactam XII to a

compound of Formula (Ia′) can be prepared by means of a free radicaldeoxygenation procedure [Barton and McCarobie, J. Chem. Soc. PerkinTrans. 1, 1574 (1975); Robins et al., J. Am Chem. Soc. 103, 933 (1981);105, 4059 (1983); Barton and Motherwell, Pure & Appl. Chem., 53, 15(1981)]. This process entails the conversion of the free hydroxy groupin compound XII to a suitable derivative, for example, a thiono-esterXIII. Upon treatment with a hydrogen radical source in the presence of aradical initiator, compound XIII undergoes reductive deoxygenation tofurnish compounds of general structure (Ia′). For such deoxygenationreactions, suitable sources of hydrogen radicals are the trialkyltinhydrides (e.g. tributyltin hydride) or tris (trialkylsilyl) silanes(e.g. (Me₃Si)₃SiH) [Schummer and Hofle, Syn. Lett. 106 (1990); Ballestriet al., J. Org. Chem. 56, 678 (1991)], and suitable radical initiatorsare provided by azaisobutyronitrile (AIBN), heat, or irradiation. Acompound of Formula (Ia′) can be alkylated using standard bases, forexample LDA, NaH, or NaHMDS, to deprotonate the amide followed byaddition of an alkylating agent with an appropriate leaving group (LG)for example halide, mesylate, or triflate, in an appropriate solvent toprovide a compound of Formula (I′) with an R⁶ substituent.

Aldol derivatives X (Scheme 2) can be prepared by the procedure of Evans(D. A. Evans et al, Org. Synth. 1990, 68, 83-90). Acylation of anoxazolidinone XIV with an acid chloride provides acylated oxazolidinoneXV. The reaction of XV with an aldehyde Q′CHO in the presence of dibutylboron triflate gives an aldol product XVI. The chiral auxiliary of thealdol product XVI is then removed to give a β-hydroxy-carboxylic acidproduct X. Additional examples are found in D. A. Evans AldrichimicaActa 1982, 15, 23-32. Alternative syntheses of compound X can beaccomplished by the methods of Crimmins (M. T. Crimmins et al, J. Am.Chem. Soc. 1997, 119, 7883-7884), Paterson (I. Paterson et al, Org.React. 1997, 51, 1-200) and Mukaiyama (T. Mukaiyama et al, Org. React.1994, 1-104).

Methods for the synthesis of lactams useful as intermediates in thesynthesis of compounds as contemplated by the present invention inlactam ring B in Formula (I), including amino benzodiazepinones, aminodibenzoazepinones and other related heterocycles, are known in the artand are disclosed in a number of references including PCT publicationnumber W098/28268, WO99/66934, and WO00/07995, which are herebyincorporated by reference. Additional references include Bock, et al, J.Org. Chem., 1987, 52, 3232-3239; Sherrill et al, J. Org. Chem., 1995,60, 730-734; and Walsh, D. A., Synthesis, September 1980, p. 677; andBrown, at. al., Tetrahedron Letters, 1971, 8, 667-670.

An example of an L-α-amino-β-thio-ε-caprolactam, as shown in Scheme 3,where ring B is the amino lactam of XVII and J is a sulfur atom has beenreported in the literature. See S. A. Ahmed et al, FEBS Letters, (1984),vol. 174, pages 76-9. One skilled in the art can extend this methodologyto the synthesis of β-amino and oxygen containing rings by analogy. Thesulfur-containing molecules can also be oxidized to the sulfoxide andsulfone by methods known to one skilled in the art.

The WXYZ-substituted amino lactam XI can be formed by alkylation of anamino lactam with WXYZ-LG. For example in Scheme 4, the α-amine ofcompound XVIII can be protected with a BOC group. The protected α-amineXVIII of the α-amino-ε-caprolactam can be prepared by methods well knownin the literature for amino protecting groups as discussed in TheodoraW. Greene's book “Protective Groups in Organic Synthesis”, like N-Bocusing di-t-butyldicarbonate in an appropriate solvent like DMSO. Thelactam nitrogen of compound XV can be alkylated by generating the anionwith bases such as LDA, lithium bis(trimethylsilyl)amide or sodiumhydride in solvents like THF, with or without cosolvents such as DMPU orHMPA and reacting this with a variety of groups containing leavinggroups (LG) like bromide, iodide, mesylate or tosylate. Alkylatingagents such as α-bromo amides, ketones and acids can be prepared by anumber of literature methods including halogenation of amino acids bydiazotization or are commercially available. Other suitable alkylatingagents such as alkyl, allylic and benzylic halides can be formed form avariety of precursors such as free-radical addition of halides oractivation of alcohols, and other chemistries known to those skilled inthe art. For discussion of these types of reactions, see Carey, F. A.and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York:Plenum Press, 1990, pages 304-305, 342-347, 695-698. The N-Bocprotecting group can be removed by any number of methods well known inthe literature like TFA in methylene chloride to give the compound XIa.

An example of the method of Scheme 1 is illustrated in the preparationof compound 5 (Scheme 5). The aldol product 3 is obtained from an aminoacid coupling of an β-hydroxyacid 1 and a benzodiazepine 2 using astandard coupling procedure. The coupled aldol product 3 is reacted withthiocarbonyl diimidazole in 1,2-dichloroethane to form a thiocarbamate4. Reduction of thiocarbamate 4 with tri-n-butyltin hydride provides abenzodiazepine 5.

Alternatively, compounds of Formula (I) can be prepared according toScheme 6. An acid XXI is coupled with a W—X—Y-Z-substituted aminolactam,XI, to give a compound of Formula (Ia) using methods commonly used inpeptide syntheses, such as DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU andphenyl ester mediated coupling, as described in A. R. Chamberlin, Chem.Rev. 1997, 97, 2243-2266. Subsequently, the amide nitrogen of compound(Ia) can optionally react with an R⁶-LG to give a compound of Formula(I).

An example of the method of Scheme 6 is illustrated in the preparationof compound 7 (Scheme 7). Carboxylic acid of formula 6 (commerciallyavailable) is coupled with 3-amino-1,4-benzodiazepin-2-one 2 (Sherrilland Sugg, J. Org. Chem. 1995, 60, 730-734, Bock et al., J. Med. Chem.,1993, 36 4276-4292) in the presence of EDC and HOBt to give compound 7(S. Nozaki et al, Bull. Chem. Soc. Jpn. 1982, 55, 2165-2168). Generalmethods for preparing compounds similar to compound 6 can be found inEvans, D. A., et al., J. Am. Chem. Soc. 1990, 112, 5290, Evans, D. A.Aldrichimica Acta 1982, 15, 23, and Ponpipom, M. M., Hagmann, W. KTetrahedron 1999, 55, 6749.

Another example of the method of Scheme 6 is illustrated in thepreparation of compound 12 (Scheme 8). In step 3′, a chiral lactic acidderivative 10 is coupled with7-amino-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin 11 in thepresence of HOBt and EDC to afford compound 12.

Compound 11 can be prepared by the methods describe in PCT patentapplication WO 99/32453. The chiral lactic acid derivative 10 isprepared from bis-alkylation of (2S)-2-hydroxy-4-methylpentanoic acid 8with iodopentane to give the lactate 2 in step 1′. Subsequent hydrolysisof lactate 2 using LiOH in THF/H₂O affords the chiral lactic acidderivative 10 in step 2′. Alternatively, compound 10 and other similarchiral lactic acid derivatives can be prepared by the methods describedin J. Org. Chem., 1986,51, 2402, and Chem. Rev., 1992,92, 919.

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows:“DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, “TBTU” forO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,“BOP” for benzotriazol-1-yloxytris-(dimethylamino)-phosphoniumhexafluorophosphate, “NMM” for N-methylmorpholine, “EDC” for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlordie, “HOBt” for1-hydroxybenzotriazole hydrate, “TEA” for triethyl amine, “LiHMDS” forlithium bis(trimethylsilyl)amide, “HMPA” for hexamethylphosphoramide,“LDA” for lithium diisopropylamide, “DCC” for1,3-dicyclohexylcarbodiimide, “PyBoP” forbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate,and “HATU” for O-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluroniumhexafluorophosphate. “HPLC” is an abbreviation used herein for highpressure liquid chromatography.

Compounds of the present invention are generally purified by HPLC usingconditions known to one skilled in the art. If necessary, organic layerscan be dried over sodium sulfate unless otherwise indicated. However,unless otherwise indicated, the following conditions are generallyapplicable.

HPLC Condition A:

Reverse-phase HPLC can be carried out using a Vydac C-18 column withgradient elution from 10% to 100% buffer B in buffer A (buffer A: watercontaining 0.1% trifluoroacetic acid, buffer B: 10% water, 90%acetonitrile containing 0.1% trifluoroacetic acid).

HPLC Condition B:

Alternatively, reverse-phase HPLC can be carried out using a Vydac C-18column with gradient elution from 10% to 90% acetonitrile in water.

Example 1(3S)-3-[(1-oxo-(2S)-2-cyclopropylmethyl-heptyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Step 1: Preparation of compound3(S)-[(1-oxo-(2R)-2-cyclopropylmethyl-(3S)-3-hydroxy-heptyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one,3. Compound 2 (Scheme 5) was prepared according to the method describedin 1) Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; 2) Bock etal., J. Med. Chem., 1993, 36, 4276-4292; and 3) Paul J. Reider et al J.Org. Chem. 1987, 52, 955. Compound 1 was prepared by the procedure ofEvans D. A. Evans et al, Org. Synth. 1990, 68, 83-90 (See Scheme 2, Q′is n-Bu and R⁵ is cyclopropylmethyl). A mixture of acid 1 (100 mg, 0.500mmol) and a camphorsulphonate salt of compound 2 (249 mg, 0.500 mmol) in2 mL of methylene chloride was stirred at 0° C. 1-Hydroxybenzotriazolehydrate (81 mg, 0.60 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg,1.00 mmol) and triethylamine (0.29 mL, 2.1 mmol) were addedsequentially. After the mixture was stirred for 16 h, 30 mL of ethylacetate was added. The organic layer was washed with 5% NaHCO₃ (30 mL)and brine (30 mL), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Purification by flash columnchromatography (50% ethyl acetate-hexane) afforded 130 mg (58%) ofproduct 3; MS (ESI): 448 (M+H), 470 (M+Na), 446 (M−H).

Step 2: Preparation of3(S)-[((2R)-2-cyclopropylmethyl-(3S)-3-((1-imidazolylthionyl)oxy)-1-oxoheptyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one,4.

Compound 3 (224 mg, 0.500 mmol), from step 1, and1,1′-(thiocarbonyl)-diimidazole (178 mg, 1.00 mmol) were refluxed in 5mL of 1,2-dichloroethane under nitrogen for 30 h (Scheme 5). Anadditional portion of 1,1′-(thiocarbonyl)diimidazole (180 mg, 1.00 mmol)was added, and reflux was continued for an additional 30 h. 20 mL ofethyl acetate was added. The organic layer was washed with water (30 mL)and brine (30 mL), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Purification by flashchromatography (60% ethyl acetate-hexane) afforded 198 mg (71%) of 4 asa colorless gel. ¹H NMR (300 MHz, CDCl₃) □ 8.56 (1 H. br s), 7.82 (1 H,br s), 7.24-7.64 (10 H, m), 7.04 (1 H, br s), 5.96 (1 H, m), 5.54 (1 H,d, J=7.7 Hz), 3.47 (3 H, s), 2.97 (1 H, m), 1.86-1.06 (3 H, m),1.24-1.45 (5 H, m), 0.94 (3 H, t, J=6.6 Hz), 0.81 (1 H, m), 0.50 (2 H,m), 0.13 (1 H, m), 0.06 (1 H, m); MS (APCI): 558 (M+H), 592 (M+Cl).

Step 3: Preparation of(3S)-3-[(1-oxo-(2R)-2-cyclopropylmethyl-heptyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one,5. A solution of 4 (190 mg, 0.350 mmol), from step 2, in 10 mL of dryand degassed toluene was heated to reflux. A solution of tri-n-butyltinhydride (210 mg, 0.700 mmol) in 1 mL of toluene was added dropwise over30 min. After an additional 5 h of reflux, the reaction was cooled,concentrated under reduced pressure. The crude mixture was purified byflash chromatography (elution with hexanes initially to removetin-containing materials, then with 40% ethyl acetate-hexane) to afford128 mg (85%) of compound 5 as a colorless gel. ¹H NMR (300 MHz, CDCl₃) δ7.21-7.66 (10 H, m), 5.60 (1 H, d, J=8.4 Hz), 3.47(3 H, s), 2.30 (1 H,m), 1.21-1.84 (10 H, m), 0.91 (3 H, t, J=6.2 Hz), 0.76 (1 H, m), 0.46 (2H, m), 0.06 (2 H, m); MS (ESI): 432 (M+H), 455 (M+Na), 430 (M−H).

Example 2(3S)-3-[(1-oxo-2-propyloctyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

In accordance with Scheme 7, a mixture of acid 6 (186 mg, 1.00 mmol) andthe (+)-camphorsulfonate salt of3-(S)-amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one, 2,(Paul J. Reider et al J. Org. Chem. 1987, 52, 955) (497 mg, 1.00 mmol)in 2 mL of methylene chloride was stirred at 0° C.1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added sequentially(Scheme 7). After the mixture was stirred for 16 h, 30 mL of ethylacetate was added. The organic layer was washed with saturated aqueousNa₂CO₃ (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfateand concentrated under reduced pressure. Purification by chromatotron(Harrison Research, Model 8924) (15% ethyl acetate-hexane) afforded twodiastereomers 7a and 7b. A: 90 mg (21%); ¹H NMR (300 MHz, CDCl₃) δ7.20-7.65 (10 H, m), 5.58 (1 H, d, J=8.5 Hz), 3.47 (3 H, s), 2.28 (1 H,m), 1.20-1.80 (14 H, m), 0.96 (3 H, t, J=7.0 Hz), 0.87 (3 H, t, J=6.3Hz); MS (ESI): 434 (M+H), 456 (M+Na), 432 (M−H); B: 96 mg (22%); ¹H NMR(300 MHz, CDCl₃) δ 7.20-7.65 (10 H, m), 5.59 (1 H, d, J=8.4 Hz), 3.47 (3H, s), 2.28 (1 H, m), 1.20-1.80 (14 H, m), 0.91 (6 H, m); MS (ESI) 434(M+H), 456 (M+Na), 432 (M−H).

Table 1 below provides representative Examples of the compounds of thepresent invention. The compounds of Table 1 prepared by methodsdisclosed herein using appropriate reagents. TABLE 1

Example Q R5 MS 3 n-heptyl n-propyl 448.3 (M + H) 4 n-hexyl n-butyl 470(M + Na) 5 n-hexyl methyl 392.3 (M + H) 6 n-pentyl n-pentyl 448.3 (M +H) 7 n-propyl n-propyl 805.3 (2M + Na) 8 n-propyl methyl 364 (M + H)

Example 3(3S)-3-[(1-oxo-2-propylnonanyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 4(3S)-3-[(1-oxo-2-butyloctyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 5(3S)-3-[(1-oxo-2-methyloctyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 6(3S)-3-[(1-oxo-2-pentylheptanyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 7(3S)-3-[(1-oxo-2-propylpentyl)]amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 8(3S)-3-[(1oxo-2-methylpentyl)amino]-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Example 9(7S)-[(2S)-1-oxo-2-pentyloxy-4-methylpentyl]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one

Step 1: Preparation of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 2(Scheme 8). To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) andstirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6mmol). The reaction mixture was stirred at rt for additional 16 h. Thesolution was poured into water and the layers separated. The aqueouslayer was extracted with methylene chloride and the combined extractswere washed with sat'd NaHCO₃, dried over magnesium sulfate, andconcentrated to a crude product. Upon further purification, compound 2was obtained as an oil (80 mg, 4%). MS [M+H]⁺273.

Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To asolution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 2 (80 mg, 0.3mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution oflithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. Thereaction mixture was stirred at rt for 16 h. THF was removed underreduced pressure to give an yellow oil which was diluted with 10 mL of 1N HCl. The aqueous phase was extracted with CH₂Cl₂ (8×15 mL), and theextracts were combined, dried over Na₂SO₄, and concentrated to affordcompound 10 (45 mg, 74%). MS [M+H]⁺203.

Step 3: Preparation of(7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one,12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg,0.22 mmol) in CH₂Cl₂/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg,0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10min then the amine 11 (52 mg, 0.22 mmol) was added and stirring wascontinued for 1 h. The solution was poured into water and the layersseparated. The aqueous layer was extracted with methylene chloride andthe combined extracts were washed with water, 1 N HCl, sat'd NaHCO₃,dried over magnesium sulfate, and concentrated to a glassy solidcompound 12 (80 mg, 86%). MS [M+H]⁺423.

Example 103-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one

(±)-3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-onewas made from 1 and3-amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one(G. Semple et al Synth. Commun. 1996, 26, 721) according to step 1 inExample 1 . MS (ESI): 449 (M+H), 471 (M+Na), 447 (M−H). Thisdiastereomeric mixture was submitted to chiral separation on a ChiralpakAD column with 10-15% i-propanol/hexane. The 2^(nd) eluting peak wasconverted to Example 10 by the same procedures of steps 2 and 3 inExample 1. MS (ESI): 433.3 (M+H).

Example 113-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-[4-methyl(pyridin-2-yl)]-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Step 1: A solution of 2-bromo-5-picoline 11a (19.8 g, 115 mmol) and2-cyanoaniline 11b (8 g, 68 mmol) in toluene (80 mL) was cooled to −40°C. and treated with 2.5 M n-BuLi (102 mL, 253 mmol). After the addition,the reaction was warmed to 0° C. and stirred for 4.5 h. The reactionmixture was poured into 3 N HCl (75 mL) and stirred for 15 min. Theorganic portion was separated and extracted with 3 N HCl (25 mL). Theaqueous portions were washed with toluene (25 mL) and made basic by theaddition of 25% NaOH. The aqueous layer was extracted with CH₂Cl₂ (3×100mL). The organic layers were combined and dried over MgSO₄. The solidswere filtered and the solvent was removed under reduced pressure toafford 11c as a dark red oil (4.8 g, 30%).¹H NMR (500 MHz, CDCl₃) □8.50(m, 1 H), 7.70-7.60 (m, 3 H), 7.25 (m, 1 H), 6.70 (m, 1 H), 6.60 (m, 1H), 6.20 (s, 2 H), 2.35 (s, 3 H).

Step 2: Acid 11d (21 g, 64 mmol) was dissolved in THF (190 mL) andcooled to 0° C. The solution was treated with catalytic DMF (0.25 mL)and oxalyl chloride (5.5 mL, 64 mmol). After 2 h, amine 11c (9 g, 42mmol) and N-methylmorpholine (12 mL, 106 mmol) in THF (25 mL) were addedslowly to the stirred reaction mixture. The reaction was warmed to rtand stirred for 12 h. The reaction was quenched by addition of H₂O (200mL). The aqueous layer was extracted with CH₂Cl₂ (200 mL). The organiclayer was washed with sat. NaHCO₃ (100 mL) and dried over MgSO₄. Thesolids were filtered and the solvent was removed under reduced pressure.The crude material was purified by SiO₂ column chromatography elutingwith 3:6.8:0.2 Et₂O—CH₂Cl₂-Et₃N. The intermediate (10 g, 19 mmol) wasdissolved in CH₃CN (130 mL) and cooled to 0° C. The solution was treatedwith NH₃ which was bubbled through the reaction vessel for 20 min. Ayellow solid precipitated from the solution. The reaction was slowlywarmed to rt and stirred for 6 h. The excess NH₃ and CH₃CN was removedunder reduced pressure. The solid material was transferred into a flaskcontaining CH₃CN (100 mL) and acetic acid (200 mL) and stirred for 12 hat rt. The solvent was removed under reduced pressure. The material wasdissolved in CH₂Cl₂ and washed with 5% NH₄OH in H₂O (100 mL) and brine(100 mL). The organic layer was dried over MgSO₄ and filtered. Thesolvent was removed under reduced pressure. The crude material wasdissolved in CH₂Cl₂ (35 mL) and Et₂O (100 mL) was added via an additionfunnel. A white solid precipitated from the solution. The solids werefiltered and dried under reduced pressure to afford 11f as a white solid(5.4 g, 64% from 11c): ¹H NMR (300 Mz, CDCl₃) □8.40 (m, 1 H), 8.38 (m, 1H), 7.96 (m, 1 H), 7.45-7.20 (m, 8 H), 7.15 (m, 1 H), 6.95 (m, 1 H),5.35 (m, 1 H), 5.14 (m, 2 H), 2.39 (s, 3 H).

Step 3: A solution of intermediate 11f (5.4 g, 13.4 mmol) and finelyground K₂CO₃ (12.9 g, 94 mmol) in DMF (20 mL) was warmed to 50° C. Tothe solution was added MeI (1.3 mL, 20 mmol). After 2-3 h, the DMF wasremoved under reduced pressure. The crude material was dissolved inEtOAc (75 mL) and washed with H₂O (3×50 mL) and brine (50 mL). Theorganic layer was dried over MgSO₄ and filtered. The solvent was removedunder reduced pressure to afford 11g as a yellow solid (3.8 g, 68%): mp157-158° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.42 (m, 1 H), 8.05 (m, 1 H),7.55 (m, 2 H), 7.43-7.20 (m, 8 H), 6.70 (m, 1 H), 5.36 (m, 1 H), 5.13(m, 2 H), 3.42 (s, 3 H), 2.38 (s, 3 H); IR (CH₂Cl₂) 3054, 1726, 1682,1499, 1266, 1069, 739, 704 cm⁻¹; FAB MS m/z=415 [C₂₄H₂₂N₄O₃+H]⁺; HPLC96.8% t_(r)=17.23 min. using HPLC condition A.

Step 4: (±)-11g was submitted to chiral separation on a CHIRALCEL ODcolumn with 1/300/700 ratio of diethylamine/EtOH/CO₂. Only the 2^(nd)eluting peak was used in the next step.

Step 5: To a solution of the product of Step 4 (0.92 g, 2.2 mmol) inCH₂Cl₂ (11 mL) was added HBr (2.2 mL, 30% in acetic acid) and thereaction was stirred 4 h. The reaction was concentrated and azeotropedwith toluene (4×15 mL) to obtain an orange solid. The crude reactionmaterial was dissolved in DMF (20 mL) followed by addition of acid 1(0.44 g, 2.2 mmol), HATU (0.84 g, 2.2 mmol) and diisopropylethylamine(1.9 mL, 11 mmol). After stirring for 14 h the reaction was quenched byaddition of H₂O and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate (3×10 mL). The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure. The crude raction was purified by columnchromatography (ethyl acetate) to afford 11i (0.28 g, 29% for two steps)as a white solid: mp 84-102; ¹H NMR (500 Mz, CD₃OD) δ 8.36d, J=1.4 Hz, 1H), 7.93 (d, J=8.1 Hz, 1 H), 7.77 (m, 1 H), 7.65 (m, 1 H), 7.59 (m, 1H), 7.28 (m, 2 H), 5.47 (s, 1 H), 3.65 (m, 1H), 3.45 (s, 3 H), 2.59 (m,1 H), 2.41 (s, 3 H), 1.56-1.32 (m, 8 H), 0.92 (t, J=7 Hz, 3 H), 0.79 (m,1 H), 0.43 (m, 2 H), 0.07 (m, 2H); IR (KBr) 3422, 2930, 1669, 1448 cm⁻¹;API MS m/z=463 [C₂₇H₃₄N₄O₃+H]; HPLC >95%, t_(r)=12.19 min. using HPLCcondition A.

Step 6: To a solution of 11i (0.17 g, 0.4 mmol) in dichloroethane (5 mL)was added 1,1′-thiocarbonyldiimidazole (0.26 g, 1.5 mmol) indichloroethane (2 mL) and the reaction was heated to 80° C. for 12 h.After cooling, the reaction was concentrated and purified by columnchromatography (ethyl acetate) to afford 11j (0.17 g, 71%) as a paleyellow solid: ¹H NMR (500 MHz, CD₃OD) □ 8.52 (s, 1 H), 8.36 (s, 1H),7.92 (d, J=8.1 Hz, 1 H), 7.84 (t, J=1.5 Hz, 1 H) 7.77 (m, 1 H), 7.65 (m,1 H), 7.59 (m, 1 H), 7.30 (m, 2 H), 7.01 (s, 1H), 5.97 (m, 1H), 5.48 (s,1 H), 3.45 (s, 3 H), 3.29 (m, 1H), 2.41 (s, 3 H), 2.01-1.79 (m, 3 H),1.48-1.25 (m, 5 H), 0.91 (t, J=6.8 Hz, 3 H), 0.80 (m, 1 H), 0.44 (m, 2H), 0.08 (m, 2H).

Step 7: A solution of 11j (0.17 g, 0.3 mmol) in toluene (5 mL) washeated to relux and then tributyltin hydride (0.13 mL, 0.5 mmol) intoluene (2 mL) was added dropwise. After 1 h the reaction was cooled andconcentrated followed by column chromatography (hexanes, then 50:50hexanes/ethyl acetate, then 5:95 methanol/methylene chloride) to affordExample 11 (0.075 g, 57%) as a white solid: mp 71-89° C.; ¹H NMR (500MHz, CD₃OD) ●8.38 (m, 1 H), 7.96 (d, J=8.1 Hz, 1 H), 7.77 (m, 1 H), 7.65(m, 1 H), 7.59 (m, 1 H), 7.30 (m, 2 H), 5.49 (s, 1 H), 3.48 (s, 3 H),2.62 (m, 1 H), 2.41 (s, 3 H), 1.56-1.32 (m, 11 H), 0.92 (m, 3 H), 0.79(m, 1 H), 0.45 (m, 2 H), 0.08 (m, 2H); IR (KBr) 3423, 2928, 1664, 1498cm⁻¹; ES MS m/z=447 [C₂₇H₃₄N₄O₂+H]; HPLC >95%, t_(r)=20.27 min. usingHPLC condition A.

Example 123-[1-oxo-2-(S)-cyclopropylmethyl-heptyl]amino-1-methyl-5-[4-trifluoromethyl(pyridin-2-yl)]-2,3-dihydro-1H-1,4-benzodiazepin-2-one

Step 1: 12c was prepared from 12a and 12b by the same method as shownfor 11c. Compound 12c was isolated as a brown oil (6.6 g, 61%): ¹H NMR δ8.95 (s, 1 H), 8.09 (m, 1 H), 7.85 (m, 1 H), 7.55 (m, 1 H), 7.30 (m, 1H), 6.72 (m, 1 H), 6.61 (m, 1 H), 6.35 (m, 2 H).

Step 2: Acid 12d (13 g, 39 mmol) was dissolved in THF (100 mL) andcooled to 0° C. The solution was treated with catalytic DMF (0.25 mL)and oxalyl chloride (3.4 mL, 39 mmol). After 2 h, amine 12c (6.6 g, 26mmol) and N-methylmorpholine (7.2 mL, 65 mmol) in THF (31 mL) were addedslowly to the stirred reaction mixture. The reaction was warmed to rtand stirred for 12 h. The reaction was quenched by addition of H₂O (200mL). The aqueous layer was extracted with CH₂Cl₂ (200 mL). The organiclayer was washed with sat. NaHCO₃ (100 mL) and dried over MgSO₄. Thesolids were filtered and the solvent was removed under reduced pressure.The crude material was purified by SiO₂ column chromatography elutingwith 1:4 Et₂O—CH₂Cl₂. The intermediate (7.8 g, 14 mmol) was dissolved inCH₃CN (95 mL) and cooled to 0° C. The solution was treated with NH₃,which was bubbled through the reaction vessel for 20 min. The reactionwas slowly warmed to rt and stirred for 6 h. The excess NH₃ and CH₃CNwas removed under reduced pressure. The solid material was dissolved in1:2 CH₃CN-acetic acid (210 mL) and stirred for 12 h at rt. The solventwas removed under reduced pressure. The material was dissolved in CH₂Cl₂and washed with 5% NH₄OH in H₂O (100 mL) and then brine (100 mL). Theorganic later was dried over MgSO₄ and filtered. The solvent was removedunder reduced pressure. The crude material was purified by SiO₂ columnchromatography eluting with 1:3 EtOAc-CH₂Cl₂ to provide the product as adark blue amorphous solid. To the solid material was added 25%EtOAc-hexane. The solids were filtered to give 12f as a light blue solid(2.8 g, 44%): ¹H NMR (300 MHz, CDCl₃) □8.83 (m, 1 H), 8.25 (m, 1 H),8.07 (s, 1 H), 8.04 (m, 1 H), 7.56 (m, 1 H), 7.42-7.22 (m, 6 H), 7.24(m, 1 H), 7.13 (m, 1 H), 6.62 (m, 1 H), 5.45 (m, 1 H), 5.17 (m, 2 H).

Step 3: A solution of intermediate 12f (3.4 g, 7.6 mmol) and finelyground K₂CO₃ (7.3 g, 53 mmol) in DMF (11 mL) was warmed to 50° C. To thesolution was added MeI (0.71 mL, 11 mmol). After 2-3 h, the DMF wasremoved under reduced pressure. The crude material was dissolved inEtOAc (250 mL) and washed with H₂O (2×150 mL), 5% LiCl (50 mL) and brine(150 mL). The organic layer was dried over MgSO₄ and filtered. Thesolvent was removed under reduced pressure. The crude material wasdissolved in 3 mL of CH₂Cl₂ and then diluted with 100 mL of 1:1Et₂O-Hexane followed by 200 mL of hexane. The resulting solid wasfurther purified by SiO₂ column chromatography eluting with 50:40:10EtOAc-Hexane-THF to afford 12g as an off white solid (1.9 g, 55%): mp179-180° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.85 (s, 1 H), 8.32 (m, 1 H),8.03 (m, 1 H), 7.60 (m, 1 H), 7.40-7.20 (m, 8 H), 6.74 (m, 1 H), 5.41(m, 1 H), 5.15 (m, 2 H), 3.46 (s, 3 H); IR (KBr) 3422, 1723, 1687, 1604,1498, 1324, 1131, 1079, 1016 cm⁻¹; CI MS m/z=469 [C24H19F₃N₄O₃+H]⁺;HPLC >95% t_(r)=20.39 min. using HPLC condition A.

Step 4: (±)-Example 12 was submitted to chiral separation on a CHIRALPAKAD column with acetonitrile. Only the 1st eluting peak was used in thenext steps.

Using the product of step 4, the title compound was made according tothe procedures in Steps 5, 6 and 7 of Example 11. MS (ESI): 501 (M+H).

Example 133-[1-oxo-2-(S)-aminomethyl-heptyl]amino-1-methyl-(5-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-onehydrobromide

Step 1: 13a (1.07 g, 3.7 mmol) was dissolved in anhydrous CH₂Cl₂ (10 mL)and cooled to −60° C. TiCl₄ was added dropwise via a cannula to theabove solution, followed by addition of diisopropylethylamine (0.68 mL,3.9 mmol). After stirring for 1 h at −60° C., the resulting mixture wasadded a solution of N-methoxymethyl benzyl carbamate (13b, 0.94 g, 4.8mmol) in CH₂Cl₂ (5 mL) via cannula. The reaction mixture was allowed towarm up to 0° C. in 1 h, quenched with saturated NH₄Cl (aq), andextracted with CH₂Cl₂ (3×20 mL). The extracts were combined, washed withNaHCO₃ (sat'd), brine, dried (MgSO₄), filtered, and concentrated Theresidue was purified on silica gel, using 20% EtOAc-hexane, to afford13c (690 mg, 41%) as a colorless oil. MS m/z 453.4 (MH⁺).

Note: N-methoxymethyl benzyl carbamate was prepared according to C. J.Barnett et al Tetrahedron Lett. 1997, 38 (5), 735.

Titanium enolate used in the above reaction was generated according toD. A. Evans et al J. Am. Chem. Soc. 1990, 112, 8215.

Step 2: 13c (0.68 g, 1.5 mmol) was dissolved in THF (8 mL) and cooled to0° C. H₂O₂ (1.6 mL, 15 mmol) and an aqueous solution of LiOH (2 mL, 1.5M) were added dropwise to the above solution sequentially at a rate ofkeeping the internal temperature below 10° C. The resulting cloudymixture was stirred at room temperature for 16 h, re-cooled to 0° C.,and quenched with aqueous Na₂SO₃ (4 mL, 1.5 M). The mixture was stirredfor an additional 1 h, concentrated in vacuo, and washed with CH₂Cl₂(3×10 mL). The aqueous mixture was cooled in an ice-water bath,acidified to pH 2 with 6 N HCl, and extracted with EtOAc (3×10 mL). Theextracts were combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give 13d (274 mg, 62%) as a white solid.

Step 4: 13d (270 mg, 0.92 mmol), 13e (Note, 381 mg, 0.92 mmol),1-hydroxybenzotriazole hydrate (HOBT, 149 mg, 1.10 mmol) were suspendedin CH₂Cl₂ (4 mL) and cooled to 0° C.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCHCl, 353mg, 1.84 mmol) and triethylamine (0.26 mL, 1.84 mmol) were addedsubsequently. After stirring for 24 h at ambient temperature, thereaction mixture was diluted with EtOAc (20 mL), washed with water,brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified on silica gel (50% EtOAc/hexane) to afford 13f (460 mg,82%) as a white solid. MS m/z 609.5 (MH⁺). Note: (±)-13e, in Cbzprotected form, was separated on a CHIRALPAK AD column withacetonitrile. Only the 1^(st) eluting peak was converted, by the actionof hydrogen bromide, to3-amino-1-methyl-(5-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-onehydrobromide (13e)used in the above reaction.

Step 5: 13f (200 mg, 0.33 mmol) was dissolved in a solution of HBr inAcOH (2 mL, 30%) and stirred for 2 h at room temperature. The resultingmixture was triturated with Et₂O. The precipitate was filtered under N₂,thoroughly washed with Et₂O, and dried overnight under high vacuum toafford Example 13 (154 mg, 84%) as a white solid. MS (ESI) m/z 475.5(MH⁺-HBr), 553.4 ((M−H)⁻).

Example 143-[1-oxo-2-(S)-(dimethylamino)methyl-heptyl]amino-1-methyl-5-(trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one

Formaldehyde (170 mg, 1.7 mmol, 37% aqueous solution) was added to asolution of 14a (free base of Example 13, 80 mg, 0.17 mmol) andNaBH(OAc)₃ (107 mg, 0.51 mmol) in dichloroethane (1 mL) at roomtemperature. The resulting mixture was then vigorously stirredovernight, and extracted with EtOAc (3×10 mL). The extracts werecombined, washed with brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified on silica gel (1:5:100Et₃N—CH₃OH—CH₂Cl₂) to afford Example 14 (75 mg, 88%). ¹H NMR (300 MHz,CDCl₃) δ 0.86 (t, J=7 Hz, 3 H), 1.20-1.45 (m, 7 H), 1.65-1.75 (m, 1 H),2.23 (dd, J=12, 4 Hz, 1 H), 2.32 (s, 6 H), 2.45-2.55 (m, 1 H), 2.72 (dd,J=12, 11 Hz, 1H), 3.43 (s, 3 H), 5.58 (d, J=8 Hz, 1 H), 7.18-7.35 (m, 3H), 7.55-7.75 (m, 5 H), 9.21 (d, J=8 Hz, 1 H); MS (ESI) m/z 503.5 (MH⁺).

Example 153-(3-isopentyloxy-2-(R)-methyl-1-oxo-propyl)amino-1-methyl-5-(trifluoromethyl)phneyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one

The compound of Example 15 was prepared by methods disclosed hereinusing appropriate reagents.

The racemic3-amino-1-methyl-(5-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one,in Cbz protected form, was separated on a CHIRALPAK AD column withacetonitrile. Only the 1^(st) eluting peak was converted, by the actionof hydrogen bromide, to an optically pure3-amino-1-methyl-(5-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-onehydrobromide, which was used in the preparation of the title compound.MS (M+1) 490.

Table 2 demonstrates representative compounds envisaged within the scopeof the present invention. Each formulae at the start of Table 2 areintended to be paired with each entry in the table which follows.

For example the compound(7S)-[(1-oxo-(2R)-2-methylpropyl-5-hexenyl)]-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-oneis represented by Example #500-B-j, which comprises the core B, sidechain i, and entry #500.

For example the compound(3R)-[(1-oxo-(2S)-2-dimethylpropyl-5-pentenyl)]amino-7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-oneis represented by Example #502-D-ab, which comprises the core D, sidechain ab, and entry #502. TABLE 2

A

B

C

D

E

F

G

H

J

K

L

M

N

O

P

Q

R

S wherein Q and R⁵ are described, respectively, in the followingmoieties:

a

b

c

d

e

f

g

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en Ex# core Q/R5 R13 —W—X—Y—Z 500 A-S a-en H methyl 501 A-S a-en Fmethyl 502 A-S a-en Cl methyl 503 A-S a-en OH methyl 504 A-S a-en —CH₃methyl 505 A-S a-en —CH₂CH₃ methyl 506 A-S a-en —OCH₃ methyl 507 A-Sa-en —CF₃ methyl 508 A-S a-en H ethyl 509 A-S a-en F ethyl 510 A-S a-enCl ethyl 511 A-S a-en OH ethyl 512 A-S a-en —CH₃ ethyl 513 A-S a-en—CH₂CH₃ ethyl 514 A-S a-en —OCH₃ ethyl 515 A-S a-en —CF₃ ethyl 516 A-Sa-en H i-propyl 517 A-S a-en F i-propyl 518 A-S a-en Cl i-propyl 519 A-Sa-en OH i-propyl 520 A-S a-en —CH₃ i-propyl 521 A-S a-en —CH₂CH₃i-propyl 522 A-S a-en —OCH₃ i-propyl 523 A-S a-en —CF₃ i-propyl 524 A-Sa-en H n-propyl 525 A-S a-en F n-propyl 526 A-S a-en Cl n-propyl 527 A-Sa-en OH n-propyl 528 A-S a-en —CH₃ n-propyl 529 A-S a-en —CH₂CH₃n-propyl 530 A-S a-en —OCH₃ n-propyl 531 A-S a-en —CF₃ n-propyl 532 A-Sa-en H n-butyl 533 A-S a-en F n-butyl 534 A-S a-en Cl n-butyl 535 A-Sa-en OH n-butyl 536 A-S a-en —CH₃ n-butyl 537 A-S a-en —CH₂CH₃ n-butyl538 A-S a-en —OCH₃ n-butyl 539 A-S a-en —CF₃ n-butyl 540 A-S a-en Hi-butyl 541 A-S a-en F i-butyl 542 A-S a-en CI i-butyl 543 A-S a-en OHi-butyl 544 A-S a-en —CH₃ i-butyl 545 A-S a-en —CH₂CH₃ i-butyl 546 A-Sa-en —OCH₃ i-butyl 547 A-S a-en —CF₃ i-butyl 548 A-S a-en H s-butyl 549A-S a-en F s-butyl 550 A-S a-en Cl s-butyl 551 A-S a-en OH s-butyl 552A-S a-en —CH₃ s-butyl 553 A-S a-en —CH₂CH₃ s-butyl 554 A-S a- en —OCH₃s-butyl 555 A-S a-en —CF₃ s-butyl 556 A-S a-en H t-butyl 557 A-S a-en Ft-butyl 558 A-S a-en Cl t-butyl 559 A-S a-en OH t-butyl 560 A-S a-en—CH₃ t-butyl 561 A-S a-en —CH₂CH₃ t-butyl 562 A-S a-en —OCH₃ t-butyl 563A-S a-en —CF₃ t-butyl 564 A-S a-en H allyl 565 A-S a-en F allyl 566 A-Sa-en Cl allyl 567 A-S a-en OH allyl 568 A-S a-en —CH₃ allyl 569 A-S a-en—CH₂CH₃ allyl 570 A-S a-en —OCH₃ allyl 571 A-S a-en —CF₃ allyl 572 A-Sa-en H cyclopropyl 573 A-S a-en F cyclopropyl 574 A-S a-en Clcyclopropyl 575 A-S a-en OH cyclopropyl 576 A-S a-en —CH₃ cyclopropyl577 A-S a-en —CH₂CH₃ cyclopropyl 578 A-S a-en —OCH₃ cyclopropyl 579 A-Sa-en —CF₃ cyclopropyl 580 A-S a-en —CF₃ cyclopropyl 581 A-S a-en Hcyclopropyl-CH₂— 582 A-S a-en F cyclopropyl-CH₂— 583 A-S a-en Clcyclopropyl-CH₂— 584 A-S a-en OH cyclopropyl-CH₂— 585 A-S a-en —CH₃cyclopropyl-CH₂— 586 A-S a-en —CH₂CH₃ cyclopropyl-CH₂— 587 A-S a-en—OCH₃ cyclopropyl-CH₂— 588 A-S a-en —CF₃ cyclopropyl-CH₂— 589 A-S a-en Hcyclobutyl 590 A-S a-en F cyclobutyl 591 A-S a-en Cl cyclobutyl 592 A-Sa-en OH cyclobutyl 593 A-S a-en —CH₃ cyclobutyl 594 A-S a-en —CH₂CH₃cyclobutyl 595 A-S a-en —OCH₃ cyclobutyl 596 A-S a-en —CF₃ cyclobutyl597 A-S a-en H cyclobutyl-CH₂— 598 A-S a-en F cyclobutyl-CH₂— 599 A-Sa-en Cl cyclobutyl-CH₂— 600 A-S a-en OH cyclobutyl-CH₂— 601 A-S a-en—CH₃ cyclobutyl-CH₂— 602 A-S a-en —CH₂CH₃ cyclobutyl-CH₂— 603 A-S a-en—OCH₃ cyclobutyl-CH₂— 604 A-S a-en —CF₃ cyclobutyl-CH₂— 605 A-S a-en Hcyclopentyl 606 A-S a-en F cyclopentyl 607 A-S a-en Cl cyclopentyl 608A-S a-en OH cyclopentyl 609 A-S a-en —CH₃ cyclopentyl 610 A-S a-en—CH₂CH₃ cyclopentyl 611 A-S a-en —OCH₃ cyclopentyl 612 A-S a-en —CF₃cyclopentyl 613 A-S a-en H cyclopentyl-CH₂— 614 A-S a-en Fcyclopentyl-CH₂— 615 A-S a-en Cl cyclopentyl-CH₂— 616 A-S a-en OHcyclopentyl-CH₂— 617 A-S a-en —CH₃ cyclopentyl-CH₂— 618 A-S a-en —CH₂CH₃cyclopentyl-CH₂— 619 A-S a-en —OCH₃ cyclopentyl-CH₂— 620 A-S a-en —CF₃cyclopentyl-CH₂— 621 A-S a-en H cyclohexyl 622 A-S a-en F cyclohexyl 623A-S a-en Cl cyclohexyl 624 A-S a-en OH cyclohexyl 625 A-S a-en —CH₃cyclohexyl 626 A-S a-en —CH₂CH₃ cyclohexyl 627 A-S a-en —OCH₃ cyclohexyl628 A-S a-en —CF₃ cyclohexyl 629 A-S a-en H cyclohexyl-CH₂— 630 A-S a-enF cyclohexyl-CH₂— 631 A-S a-en Cl cyclohexyl-CH₂— 632 A-S a-en OHcyclohexyl-CH₂— 633 A-S a-en —CH₃ cyclohexyl-CH₂— 634 A-S a-en —CH₂CH₃cyclohexyl-CH₂— 635 A-S a-en —OCH₃ cyclohexyl-CH₂— 636 A-S a-en —CF₃cyclohexyl-CH₂— 637 A-S a-en H phenyl 638 A-S a-en F phenyl 639 A-S a-enCl phenyl 640 A-S a-en OH phenyl 641 A-S a-en —CH₃ phenyl 642 A-S a-en—CH₂CH₃ phenyl 643 A-S a-en —OCH₃ phenyl 644 A-S a-en —CF₃ phenyl 645A-S a-en H 2-F-phenyl 646 A-S a-en F 2-F-phenyl 647 A-S a-en Cl2-F-phenyl 648 A-S a-en OH 2-F-phenyl 649 A-S a-en —CH₃ 2-F-phenyl 650A-S a-en —CH₂CH₃ 2-F-phenyl 651 A-S a-en —OCH₃ 2-F-phenyl 652 A-S a-en—CF₃ 2-F-phenyl 653 A-S a-en H 3-F-phenyl 654 A-S a-en F 3-F-phenyl 655A-S a-en Cl 3-F-phenyl 656 A-S a-en OH 3-F-phenyl 657 A-S a-en —CH₃3-F-phenyl 658 A-S a-en —CH₂CH₃ 3-F-phenyl 659 A-S a-en —OCH₃ 3-F-phenyl660 A-S a-en —CF₃ 3-F-phenyl 661 A-S a-en H 4-F-phenyl 662 A-S a-en F4-F-phenyl 663 A-S a-en Cl 4-F-phenyl 664 A-S a-en OH 4-F-phenyl 665 A-Sa-en —CH₃ 4-F-phenyl 666 A-S a-en —CH₂CH₃ 4-F-phenyl 667 A-S a-en —OCH₃4-F-phenyl 668 A-S a-en —CF₃ 4-F-phenyl 669 A-S a-en H 3-Cl-phenyl 670A-S a-en F 3-Cl-phenyl 671 A-S a-en Cl 3-Cl-phenyl 672 A-S a-en OH3-Cl-phenyl 673 A-S a-en —CH₃ 3-Cl-phenyl 674 A-S a-en —CH₂CH₃3-Cl-phenyl 675 A-S a-en —OCH₃ 3-Cl-phenyl 676 A-S a-en —CF₃ 3-Cl-phenyl677 A-S a-en H 4-Cl-phenyl 678 A-S a-en F 4-Cl-phenyl 679 A-S a-en Cl4-Cl-phenyl 680 A-S a-en OH 4-Cl-phenyl 681 A-S a-en —CH₃ 4-Cl-phenyl682 A-S a-en —CH₂CH₃ 4-Cl-phenyl 683 A-S a-en —OCH₃ 4-Cl-phenyl 684 A-Sa-en —CF₃ 4-Cl-phenyl 685 A-S a-en H 3-Me-phenyl 686 A-S a-en F3-Me-phenyl 687 A-S a-en Cl 3-Me-phenyl 688 A-S a-en OH 3-Me-phenyl 689A-S a-en —CH₃ 3-Me-phenyl 690 A-S a-en —CH₂CH₃ 3-Me-phenyl 691 A-S a-en—OCH₃ 3-Me-phenyl 692 A-S a-en —CF₃ 3-Me-phenyl 693 A-S a-en H4-Me-phenyl 694 A-S a-en F 4-Me-phenyl 695 A-S a-en Cl 4-Me-phenyl 696A-S a-en OH 4-Me-phenyl 697 A-S a-en —CH₃ 4-Me-phenyl 698 A-S a-en—CH₂CH₃ 4-Me-phenyl 699 A-S a-en —OCH₃ 4-Me-phenyl 700 A-S a-en —CF₃4-Me-phenyl 701 A-S a-en H 3-MeO-phenyl 702 A-S a-en F 3-MeO-phenyl 703A-S a-en Cl 3-MeO-phenyl 704 A-S a-en OH 3-MeO-phenyl 705 A-S a-en —CH₃3-MeO-phenyl 706 A-S a-en —CH₂CH₃ 3-MeO-phenyl 707 A-S a-en —OCH₃3-MeO-phenyl 708 A-S a-en —CF₃ 3-MeO-phenyl 709 A-S a-en H 4-MeO-phenyl710 A-S a-en F 4-MeO-phenyl 711 A-S a-en Cl 4-MeO-phenyl 712 A-S a-en OH4-MeO-phenyl 713 A-S a-en —CH₃ 4-MeO-phenyl 714 A-S a-en —CH₂CH₃4-MeO-phenyl 715 A-S a-en —OCH₃ 4-MeO-phenyl 716 A-S a-en —CF₃4-MeO-phenyl 717 A-S a-en H 3-F₃C-phenyl 718 A-S a-en F 3-F₃C-phenyl 719A-S a-en Cl 3-F₃C-phenyl 720 A-S a-en OH 3-F₃C-phenyl 721 A-S a-en —CH₃3-F₃C-phenyl 722 A-S a-en —CH₂CH₃ 3-F₃C-phenyl 723 A-S a-en —OCH₃3-F₃C-phenyl 724 A-S a-en —CF₃ 3-F₃C-phenyl 725 A-S a-en H 4-F₃C-phenyl726 A-S a-en F 4-F₃C-phenyl 727 A-S a-en Cl 4-F₃C-phenyl 728 A-S a-en OH4-F₃C-phenyl 729 A-S a-en —CH₃ 4-F₃C-phenyl 730 A-S a-en —CH₂CH₃4-F₃C-phenyl 731 A-S a-en —OCH₃ 4-F₃C-phenyl 732 A-S a-en —CF₃4-F₃C-phenylUtility

Aβ production has been implicated in the pathology of Alzheimer'sDisease (AD). The compounds of the present invention have utility forthe prevention and treatment of AD by inhibiting Aβ production. Methodsof treatment target formation of Aβ production through the enzymesinvolved in the proteolytic processing of β amyloid precursor protein.Compounds that inhibit β or γ secretase activity, either directly orindirectly, control the production of Aβ. Such inhibition of β or γsecretases reduces production of A

and is expected to reduce or prevent the neurological disordersassociated with A

protein, such as Alzheimer's Disease.

Cellular screening methods for inhibitors of A

production, testing methods for the in vivo suppression of Aβproduction, and assays for the detection of secretase activity are knownin the art and have been disclosed in numerous publications, includingJ. Med. Chem. 1999, 42, 3889-3898, PCT publication number WO 98/22493,EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat.No. 5,593,846; all thereby incorporated by reference.

The compounds of the present invention have utility for the preventionand treatment of disorders involving Aβ production, such ascerebrovascular disorders.

Compounds of Formula (I) are expected to possess γ-secretase inhibitoryactivity. The γ-secretase inhibitory activity of the compounds of thepresent invention is demonstrated using assays for such activity, forexample, using the assay described below. Compounds of the presentinvention have been shown to inhibit the activity of γ-secretase, asdetermined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit A□ production. These would be provided in commercial kitscomprising a compound of this invention.

As used herein “jag” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM”]denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS”denotes sodium dodecyl sulfate, and “DMSO” dimethyl sulfoxide, and“EDTA” denotes ethylenediaminetetraacetic acid.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 100 μM for the inhibition of Aβ production.Preferrably the IC₅₀ or K_(i) value is less than about 10 μM; morepreferrably the IC₅₀ or K_(i) value is less than about 0.1 μM. Compoundsof the present invention have been shown to inhibit Aβ proteinproduction with an IC₅₀ or K_(i) value of less than 100 μM.

β Amyloid Precursor Protein Accumulation Assay

A novel assay to evaluate the accumulation of Aβ protein was developedto detect potential inhibitors of secretase. The assay uses the N 9 cellline, characterized for expression of exogenous APP by immunoblottingand immunoprecipitation.

The effect of test compounds on the accumulation of Aβ in theconditioned medium is tested by immunoprecipitation. Briefly, N 9 cellsare grown to confluency in 6-well plates and washed twice with 1× Hank'sbuffered salt solution. The cells are starved in methionine/cysteinedeficient media for 30 min, followed by replacement with fresh deficientmedia containing 150 uCi S35 Translabel (Amersham). Test compoundsdissolved in DMSO (final concentration 1%) are added together with theaddition of radiolabel. The cells are incubated for 4 h at 37° C. in atissue culture incubator.

At the end of the incubation period, the conditioned medium is harvestedand pre-cleared by the addition of 5 μl normal mouse serum and 50ul ofprotein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30minutes at 4° C., followed by a brief centrifugation in a microfuge. Thesupernatant is then harvested and transferred to fresh tubes containing5 ug of a monoclonal antibody (clone 1101.1; directed against aninternal peptide sequence in Aβ) and 50 μl protein A Sepharose. Afterincubation overnight at 4° C., the samples are washed three times withhigh salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA,0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris,pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times withlOmM Tris, pH 7.5. The pellet after the last wash is resuspended in SDSsample buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatantis then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5%Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film oranalyzed by phosphorimaging. The resulting image is analyzed for thepresence of Aβ polypeptides. The steady-state level of Aβ in thepresence of a test compound is compared to wells treated with DMSO (1%)alone. A typical test compound blocks Aβ accumulation in the conditionedmedium, and is therefore considered active, with an IC₅₀ less than 100μM.

C-Terminus β Amyloid Precursor Protein Accumulation Assay

The effect of test compounds on the accumulation of C-terminal fragmentsis determined by immunoprecipitation of APP and fragments thereof fromcell lysates. N 9 cells are metabolically labeled as above in thepresence or absence of test compounds. At the end of the incubationperiod, the conditioned medium are harvested and cells lysed in RIPAbuffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate,0.1% SDS, 150 mM NaCl, 0.125% NaN₃). Again, lysates are precleared with5 ul normal rabbit serum/50 ul protein A Sepharose, followed by theaddition of BC-1 antiserum (15 μl;) and 50 μl protein A Sepharose for 16hours at 4° C. The immunoprecipitates are washed as above, boundproteins eluted by boiling in SDS sample buffer and fractionated byTris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager,the resulting images are analyzed for the presence of C-terminal APPfragments. The steady-state level of C-terminal APP fragments iscompared to wells treated with DMSO (1%) alone. A typical test compoundstimulates C-terminal fragment accumulation in the cell lysates, and istherefore considered active, with an IC₅₀ less than 100 μM.

Aβ Immunoprecipitation Assay

This immunoprecipitation assay is specific for γ secretase (i.e.,proteolytic activity required to generate the C-terminal end of Aβeither by direct cleavage or generating a C-terminal extended specieswhich is subsequently further proteolyzed). N 9 cells are pulse labeledin the presence of a reported γ secretase inhibitor (MDL 28170) for 1 h,followed by washing to remove radiolabel and MDL 28170. The media isreplaced and test compounds are added. The cells are chased forincreasing periods of times and Aβ is isolated from the conditionedmedium and C-terminal fragments from cell lysates (see above). The testcompounds are characterized whether a stabilization of C-terminalfragments is observed and whether Aβ is generated from these accumulatedprecursor. A typical test compound prevents the generation of Aβ out ofaccumulated C-terminal fragments and is considered active with an IC₅₀less than 100 μM.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed to prevent or treat neurological disorders related to β-amyloidproduction or accumulation, such as Alzheimer's disease and Down'sSyndrome.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a host, such as a human or a mammal. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, socium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspaitamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein: Q is—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—S—R⁴, —(CR⁷R^(7a))_(n)—O—R⁴,—(CR⁷R^(7a))_(m)—N(R^(7b))—R⁴, —(CR⁷R^(7a))_(n)—S(═O)—R⁴,—(CR⁷R^(7a))_(n)—S(═O)₂—R⁴, or —(CR⁷R^(7a))_(n)—C(═O)—R⁴; provided whenn is 0, then R⁴ is not H; m is 1, 2, or 3; n is 0, 1, or 2; R⁴ is H,C₁-C₈ alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with0-3 R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,OR^(14a), OR²², SR²², C(═O)OR²², NR²¹R²², S(═O)R²², S (═O)₂R²², C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3R^(5b); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5b), ateach occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁶ is H; C₁-C₆alkyl substituted with 0-3 R^(6a); C₃-C₁₀ carbocycle substituted with0-3 R^(6b); or aryl substituted with 0-3 R^(6b); R^(6a), at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F,Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, aryl or CF₃; R^(6b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R⁷, ateach occurrence, is independently H or C₁-C₄ alkyl; R^(7a), at eachoccurrence, is independently H or C₁-C₄ alkyl; R^(7b) is H or C₁-C₄alkyl; Ring B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W isa bond or —(CR⁸R^(8a))_(p)—; p is 0, 1, 2, 3, or 4; R⁸ and R^(8a), ateach occurrence, are independently selected from H, F, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈ cycloalkyl; X is a bond; arylsubstituted with 0-3 R^(Xb); C₃-C₁₀ carbocycle substituted with 0-3R^(Xb); or 5 to 10 membered heterocycle substituted with 0-2 R^(Xb);R^(Xb), at each occurrence, is independently selected from H, OH, C1, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄halothioalkoxy; Y is a bond or (CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is0, 1, or 2; u is 0, 1, or 2; R⁹ and R^(9a), at each occurrence, areindependently selected from H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; V isa bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—,NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—,—S(═O)NR^(19b)—, —C(═O)O—, or —OC(═O)—; Z is H; C₁-C₈ alkyl substitutedwith 0-3 R^(12a); C₂-C₆ alkenyl substituted with 0-3 R^(12a); C₂-C₆alkynyl substituted with 0-3 R^(12a); aryl substituted with 0-4 R^(12b);C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH3, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, aryl, C₃-C₆cycloalkyl, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) is H, phenyl, benzyl, orC₁-C₄ alkyl; R¹⁵, at each occurrence, is independently selected from H,C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—; R¹⁶, at each occurrence, is independently selected fromH, OH, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—; alternatively, R¹⁵ and R¹⁶, together with the nitrogento which they are attached, may combine to form a 4-7 membered ringwherein said 4-7 membered ring optionally contains an additionalheteroatom selected from 0 or NH; R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆alkoxyalkyl, aryl substituted by 0-4 R^(17a), or —CH₂-aryl substitutedby 0-4 R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃,SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,(C₁-C6 alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—;R^(19b), at each occurrence, is independently is H or C₁-C₄ alkyl; R²¹is H, phenyl, benzyl, or C₁-C₄ alkyl; and R²² is C₁-C₄ alkyl, C₂-C₄alkenyl, or C₃-C₄ alkynyl.
 2. A compound, according to claim 1, ofFormula (I) or a pharmaceutically acceptable salt thereof, wherein: Q is—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—S—R⁴, —(CR⁷R^(7a))_(n)—O—R⁴, or—(CR⁷R^(7a))_(m)—N(R^(7b))—R⁴; m is 1 or 2; n is 0 or 1; R⁴ is H, C₁-C₈alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with 0-3R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,OR^(14a), C(═O)OR²², SR²², OR²², NR²¹R²², S(═O)R²², S(═O)₂R²², C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3R^(5b); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5b), ateach occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁶ is H,methyl, or ethyl; R⁷, at each occurrence, is independently H or C₁-C₄alkyl; R^(7a), at each occurrence, is independently H or C₁-C₄ alkyl;R^(7b) is H or C₁-C₄ alkyl; Ring B is:

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W isa bond or —(CH₂)_(p)—; p is 1 or 2; X is a bond; phenyl substituted with0-2 R^(Xb); C₃-C₆ carbocycle substituted with 0-2 R^(Xb); or 5 to 6membered heterocycle substituted with 0-2 R^(Xb), R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃alkoxy, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, and C₁-C₃ halothioalkoxy; Yis a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,—C(═O)NR^(19b), —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,—NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or —OC(═O)—; Z is H; C₁-C₈alkyl substituted with 0-3 R^(12a); C₂-C₆ alkenyl substituted with 0-3R^(12a); C₂-C₆ alkynyl substituted with 0-3 R^(12a); aryl substitutedwith 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) isH, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; alternatively, R¹⁵ andR¹⁶, together with the nitrogen to which they are attached, may combineto form a 4-7 membered ring wherein said 4-7 membered ring optionallycontains an additional heteroatom selected from O or NH; R¹⁷ is H, C₁-C₆alkyl, C₂-C₆ alkoxyalkyl, aryl substituted by 0-4 R^(17a), or —CH₂-arylsubstituted by 0-4 R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,S(O)CH₃, SO₂CH₃, —NH₂, —N(C₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹,at each occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, phenyl, benzyl, phenethyl; R^(19b), at each occurrence,is independently is H or C₁-C₄ alkyl; R²¹ is H, phenyl, benzyl, or C₁-C₄alkyl; and R²² is C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₃-C₄ alkynyl. 3.(canceled)
 4. A compound according to claim 2 of Formula (I) or apharmaceutically acceptable salt thereof, wherein: Q is —(CH₂)_(m)—R⁴,—(CH₂)_(n)—S—R⁴, —(CH₂)_(n)—O—R⁴, or —(CH₂)_(m)—N(H)—R⁴; m is 1 or 2; nis 0 or 1; R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenylsubstituted with 0-3 R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a),C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), aryl substituted with 0-3R^(4b), or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b); R^(4a), at eachoccurrence, is independently selected from is H, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR²², OR^(14a), NR²¹R²², S(═O)R²²,S(═O)₂R²², C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,C₁-C₄ haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3R^(5b); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5b), ateach occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃,Cl, F, Br, I, ═O, CN, NO₂, R¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy; Ring B is:

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-6 alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W isa bond; X is a bond; Y is a bond; Z is H; C₁-C₈ alkyl substituted with0-3 R^(12a); C₂-C₆ alkenyl substituted with 0-3 R^(12a); or C₂-C₆alkynyl substituted with 0-3 R^(12a); R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); and whereinsaid 5 to 10 membered heterocycle is selected from pyridinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl,benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,benzoxazolinyl, quinolinyl, and isoquinolinyl; R^(12b), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³ ₁at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) isH, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄ alkyl)-S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄ alkyl)-S(═O)₂—; and alternatively, R¹⁵and R¹⁶, together with the nitrogen to which they are attached, maycombine to form a 4-6 membered ring wherein said 4-6 membered ringoptionally contains an additional heteroatom selected from O or NH,wherein said 4-6 membered ring is selected from imidazolidinyl,oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, andthiomorpholinyl; R¹⁸, at each occurrence, is independently selected fromH, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and(C₁-C₆ alkyl)-S(═O)₂—; R¹⁹, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl,phenethyl; R²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;and R²² is methyl, ethyl, propyl, butyl, propenyl, butenyl, andpropargyl.
 5. A compound or a pharmaceutically acceptable salt thereof,according to claim 4 wherein: Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴; R⁴ isC₁-C₆ alkyl substituted with 0-3 R^(4a), C₂-C₆ alkenyl substituted with0-3 R^(4a), C₂-C₆ alkynyl substituted with 0-3 R^(4a), C₃-C₆ carbocyclesubstituted with 0-3 R^(4b), phenyl substituted with 0-3 R^(4b), or 5 to6 membered heterocycle containing 1 to 3 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,C(═O)OR²², SR²², OR^(14a), OR²², NR²¹R²², S(═O)R²², S(═O)₂R²², C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); or C₂-C₆ alkynyl substituted with0-3 R^(5b); R^(5b), at each occurrence, is independently selected from:H, methyl, ethyl, propyl, butyl, CF₃, Cl, F, Br, I, =O; C₃-C₆ carbocyclesubstituted with 0-3 R^(5c); phenyl substituted with 0-3 R^(5c); or 5 to6 membered heterocycle containing 1 to 3 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; Ring B is:

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂C₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W isa bond; X is a bond; Y is a bond; Z is H; C₁-C₄ alkyl substituted with0-3 R^(12a); C₂-C₄ alkenyl substituted with 0-3 R^(12a); or C₂-C₄alkynyl substituted with 0-3 R^(12a); R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; R¹³, at each occurrence, is independently selectedfrom H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,and CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence,is independently selected from H, C₁-C₄ alkyl, and benzyl; R¹⁶, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—,and ethyl-S(═O)₂—; R¹⁸, at each occurrence, is independently selectedfrom H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;R¹⁹, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl; R²¹ is H, phenyl, benzyl, methyl, ethyl,propyl, or butyl; and R²² is methyl, ethyl, propyl, butyl, propenyl,butenyl, and propargyl.
 6. A compound according to claim 5 or apharmaceutically acceptable salt or prodrug thereof wherein: Q is—CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴; R⁴ is C₁-C₆ alkyl substituted with 0-2R^(4a), C₂-C₆ alkenyl substituted with 0-2 R^(4a), C₂-C₆ alkynylsubstituted with 0-2 R^(4a), or C₃-C₆ cycloalkyl substituted with 0-3R^(4b); R^(4a), at each occurrence, is independently selected from is H,OH, F, Cl, Br, I, CN, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, methoxy,ethoxy, propoxy, OCF₃; C₃-C₆ carbocycle substituted with 0-3 R^(4b),phenyl substituted with 0-3 R^(4b), or 5 to 6 membered heterocyclecontaining 1 to 3 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 6 membered heterocycle is substituted with0-3 R^(4b); wherein said 5 to 6 membered heterocycle is selected frompyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, and tetrazolyl; R^(4b), at each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵ is H; C₁-C₄ alkyl substitutedwith 0-1 R^(5b); C₂-C₄ alkenyl substituted with 0-1 R^(5b); or C₂-C₄alkynyl substituted with 0-1 R^(5b); R^(5b), at each occurrence, isindependently selected from: H, methyl, ethyl, propyl, butyl, CF₃; C₃-C₆carbocycle substituted with 0-2 R^(5c); phenyl substituted with 0-3R^(5c); and 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(5c); wherein said 5 to 6membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R^(5c), ateach occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶,CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;Ring B is:

W is a bond; X is a bond; Y is a bond; Z is H; C₁-C₄ alkyl substitutedwith 0-1 R^(12a); C₂-C₄ alkenyl substituted with 0-1 R^(12a); or C₂-C₄alkynyl substituted with 0-1 R¹²a; R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹³, at each occurrence,is independently selected from H, OH, methyl, ethyl, propyl, butyl,methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, methyl, ethyl, propyl, or butyl; R¹⁵, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, and butyl; andR¹⁶, at each occurrence, is independently selected from H, OH, methyl,ethyl, propyl, butyl, benzyl, and phenethyl; R¹⁸, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl, and phenethyl; and R¹⁹, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, and butyl.
 7. A compound or apharmaceutically acceptable salt thereof, according to claim 6 wherein:R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂N(CH₃)₂,—CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂N(CH₂CH₃)₂,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, or—CH₂CH₂-cyclohexyl; Q is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH2CH(C₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH(C₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH(CH₃)₂,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl,—CH₂CH₂-cyclohexyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—OCH₂CH₂CH₂CH₃, —OCH₂CH(CH₃)_(2,) —OCH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH₃,—OCH₂CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH(CH₃)₂,—OCH₂-cyclopropyl, —OCH₂-cyclobutyl, —OCH₂-cyclopentyl,—OCH₂-cyclohexyl, —OCH₂CH₂-cyclopropyl, —OCH₂CH₂-cyclobutyl,—OCH₂CH₂-cyclopentyl, —OCH₂CH₂-cyclohexyl, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃,—CH₂—OCH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₃, —CH₂OCH₂CH(CH₃)₂,—CH₂OCH₂CH₂CH₂CH₂CH₃, —CH₂OCH₂CH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH(CH₃)₂,—CH₂O-cyclopropyl, —CH₂O-cyclobutyl, —CH₂O-cyclopentyl,—CH₂O-cyclohexyl, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂-cyclobutyl,—CH₂OCH₂-cyclopentyl, —CH₂OCH₂-cyclohexyl; —CH₂(NH)CH₃, —CH₂(NH)CH₂CH₃,—CH₂(NH)CH₂CH₂CH₃, —CH₂—(NH)CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₃,—CH₂(NH)CH₂CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH₂CH(CH₃)₂,—CH₂(NH)CH₂CH₂CH₂CH(CH₃)₂, —CH₂(NH)-cyclopropyl, —CH₂(NH)-cyclobutyl,—CH₂(NH)-cyclopentyl, —CH₂(NH)-cyclohexyl, —CH₂(NH)CH₂-cyclopropyl,—CH₂(NH)CH₂-cyclobutyl, —CH₂(NH)CH₂-cyclopentyl, or—CH₂(NH)CH₂-cyclohexyl; W is a bond; X is a bond; Y is a bond; Z ismethyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl,or allyl; R¹³, at each occurrence, is independently selected from H, F,Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.
 8. A compound according to claim2 of Formula (I) or a pharmaceutically acceptable salt thereof wherein:Q is —(CH₂)_(m)—R⁴, —(CH₂)_(n)—S—R⁴, —(CH₂)_(n)—O—R⁴, or—(CH₂)_(m)—N(H)—R⁴; m is 1 or 2; n is 0 or 1; R⁴ is C₁-C₈ alkylsubstituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with 0-3 R^(4a),C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocycle substitutedwith 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,C(═O)OR²², SR²², OR²², OR^(14a), NR²¹R²², S(═O)R²², S(═O)₂R²², C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3R^(5b); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5b), ateach occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy; Ring B is selected from:

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W isa bond, —CH₂—, —CH₂CH₂—; X is a bond; phenyl substituted with 0-2R^(Xb); C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or 5 to 6 memberedheterocycle substituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R1⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—,—N(R¹⁹)—, —C(═O)NR^(19b), —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,—S(═O)₂NR^(19b)—, NR^(19b)S(═O)—, —S(═O)NR^(19b), —C(═O)O—, or —OC(═O)—;Z is C₁-C₃ alkyl substituted with 1-2 R^(12a); aryl substituted with 0-4R^(12b); C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); R^(12a), at each occurrence, isindependently selected from aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-4 R^(12b); and 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) is H, phenyl, benzyl, orC₁-C₄ alkyl; R¹⁵, at each occurrence, is independently selected from H,C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—; R¹⁶, at each occurrence, is independently selected fromH, OH, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—; and alternatively, R¹⁵ and R¹⁶, together with thenitrogen to which they are attached, may combine to form a 4-6 memberedring wherein said 4-6 membered ring optionally contains an additionalheteroatom selected from O or NH, wherein said 4-6 membered ring isselected from imidazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl,morpholinyl, and thiomorpholinyl; R¹⁸, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,(C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, phenyl, benzyl, and phenethyl; R²¹ is H, phenyl, benzyl, methyl,ethyl, propyl, or butyl; and R²² is methyl, ethyl, propyl, butyl,propenyl, butenyl, and propargyl.
 9. compound or a pharmaceuticallyacceptable salt thereof according to claim 8 wherein: Q is —CH₂R⁴,—O—R⁴, or —CH₂—NH—R⁴; R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a);C₂-C₆ alkenyl substituted with 0-3 R^(4a); C₂-C₆ alkynyl substitutedwith 0-3 R^(4a); C₃-C₆ carbocycle substituted with 0-3 R^(4b); phenylsubstituted with 0-3 R^(4b), or 5 to 6 membered heterocycle containing 1to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 6 membered heterocycle is substituted with 0-3 R^(4b); R^(4a),at each occurrence, is independently selected from H, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, C(═O)OR²², SR²², OR^(14a), OR²², NR²¹R²², S(═O)R²²,S(═O)₂R²², C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,C₁-C₄ haloalkyl-S—, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R⁵ is H; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₂-C₆alkenyl substituted with 0-3 R^(5b); or C₂-C₆ alkynyl substituted with0-3 R^(5b); R^(5b), at each occurrence, is independently selected from:H, methyl, ethyl, propyl, butyl, CF₃, Cl, F, Br, I, ═O; C₃-C₆ carbocyclesubstituted with 0-3 R^(5c); phenyl substituted with 0-3 R^(5c); or 5 to6 membered heterocycle containing 1 to 3 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; Ring B is:

W is a bond, —CH₂—, —CH₂CH₂—; X is a bond; phenyl substituted with 0-1R^(Xb); C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or 5 to 6 memberedheterocycle substituted with 0-1 R^(Xb); R^(Xb) selected from H, OH, Cl,F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃, S(═O)₂CH₃, methyl, ethyl,propyl, methoxy, ethoxy, opoxy, and —OCF₃; Y is a bond, —C(═O)—, —O—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—; Z is C₁-C₂ alkylsubstituted with 1-2 R^(12a); aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-3 R^(12b); or 5 to 10 membered heterocyclecontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 10 membered heterocycle is substituted with0-3 R^(12b); R^(12a), at each occurrence, is independently selected fromaryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; R^(14a) is H, phenyl, benzyl,or C₁-C₄ alkyl; R¹⁵, at each occurrence, is independently selected fromH, C₁-C₄ alkyl, and benzyl; R¹⁶, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—; R¹⁸, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R¹⁹, at each occurrence,is independently selected from H, methyl, ethyl, propyl, and butyl; andR²¹ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; and R²² ismethyl, ethyl, propyl, butyl, propenyl, butenyl, and propargyl.
 10. Acompound according to claim 9 or a pharmaceutically acceptable saltthereof wherein: Q is —CH₂R⁴, —O—R⁴, or —CH₂—NH—R⁴; R⁴ is C₁-C₆ alkylsubstituted with 0-2 R^(4a), C₂-C₆ alkenyl substituted with 0-2 R^(4a),C₂-C₆ alkynyl substituted with 0-2 R^(4a), or C₃-C₆ cycloalkylsubstituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, OH, F, Cl, Br, I, CN, NR¹⁵NR¹⁶, CF₃,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, OCF₃; C₃-C₆carbocycle substituted with 0-3 R^(4b), phenyl substituted with 0-3R^(4b), or 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b); wherein said 5 to 6membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵ isH; C₁-C₄ alkyl substituted with 0-1 R^(5b); C₂-C₄ alkenyl substitutedwith 0-1 R^(5b); or C₂-C₄ alkynyl substituted with 0-1 R^(5b); R^(5b),at each occurrence, is independently selected from: H, methyl, ethyl,propyl, butyl, CF₃; C₃-C₆ carbocycle substituted with 0-2 R^(5c); phenylsubstituted with 0-3 R^(5c); and 5 to 6 membered heterocycle containing1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 6 membered heterocycle is substituted with 0-3 R^(5c); whereinsaid 5 to 6 membered heterocycle is selected from pyridinyl,pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,and tetrazolyl; R^(5C), at each occurrence, is independently selectedfrom H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; Ring B is:

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)2R¹⁷;C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R_(10b); R^(10b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;W is a bond or —CH₂—; X is a bond; phenyl substituted with 0-1 R^(Xb);C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or 5 to 6 memberedheterocycle substituted with 0-1 R^(Xb); R^(Xb) selected from H, OH, Cl,F, NR¹⁵R¹⁶, CF₃, acetyl, methyl, ethyl, methoxy, ethoxy, and —OCF₃; Y isa bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or—N(CH₂CH₃)—; Z is C₁-C₂ alkyl substituted with 1-2 R^(12a); C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-3R^(12b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); R^(12a), at eachoccurrence, is independently selected from C₆-C₁₀ aryl substituted with0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); and wherein said 5 to 10 memberedheterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl,thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl; R^(12b), at each occurrence, is independentlyselected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and—OCF₃; R¹³, at each occurrence, is independently selected from H, OH,methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶,and CF₃; R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; R¹⁵,at each occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; and R¹⁶, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, benzyl, andphenethyl; R¹⁸, at each occurrence, is independently selected from H,methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R¹⁹, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl.
 11. A compound, according to claim 10, orpharmaceutically acceptable salt thereof, wherein: R⁵ is —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂N(C₃)₂, —CH₂N(CH₂CH₃)₂, —CH₂CH₂NH₂,—CH₂CH₂N(C₃)₂, —CH₂CH₂N(CH₂CH₃)₂, —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, or —CH₂CH₂-cyclohexyl; Q is—CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(C₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH(CH₃)₂,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl,—CH₂CH₂-cyclohexyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—OCH₂CH₂CH₂CH₃, —OCH₂CH(CH₃)₂, —OCH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH₃,—OCH₂CH₂CH₂CH₂CH₂CH₃, —OCH₂CH₂CH₂CH(CH₃)₂, —OCH₂CH₂CH₂CH₂CH(CH₃)₂,—OCH₂-cyclopropyl, —OCH₂-cyclobutyl, —OCH₂-cyclopentyl,—OCH₂-cyclohexyl, —OCH₂CH₂-cyclopropyl, —OCH₂CH₂-cyclobutyl,—OCH₂CH₂-cyclopentyl, —OCH₂CH₂-cyclohexyl, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃,—CH₂—OCH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH₃, —CH₂OCH₂CH(CH₃)₂,—CH₂OCH₂CH₂CH₂CH₂CH₃, —CH₂OCH₂CH₂CH(CH₃)₂, —CH₂OCH₂CH₂CH₂CH(CH₃)₂,—CH₂O-cyclopropyl, —CH₂O-cyclobutyl, —CH₂O-cyclopentyl,—CH₂O-cyclohexyl, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂-cyclobutyl,—CH₂OCH₂-cyclopentyl, —CH₂OCH₂-cyclohexyl; —CH₂(NH)CH₃, —CH₂(NH)CH₂CH₃,—CH₂(NH)CH₂CH₂CH₃, —CH₂—(NH)CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₃,—CH₂(NH)CH₂CH(CH₃)₂, —CH₂(NH)CH₂CH₂CH₂CH₂CH₃, —CH₂(NH)CH₂CH₂CH(CH₃)₂,—CH₂(NH)CH₂CH₂CH₂CH(CH₃)₂, —CH₂(NH)-cyclopropyl, —CH₂(NH)-cyclobutyl,—CH₂(NH)-cyclopentyl, —CH₂(NH)-cyclohexyl, —CH₂(NH)CH₂-cyclopropyl,—CH₂(NH)CH₂-cyclobutyl, —CH₂(NH)CH₂-cyclopentyl, or—CH₂(NH)CH₂-cyclohexyl; W is a bond or —CH₂—; X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—, Zis phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl,4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl,2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl,2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl,3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl,2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl,3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl,3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—,(2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—,(1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—,(1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—,(cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—,(N-pipridinyl)CH₂—, or (phenyl)₂CH—; R¹³, at each occurrence, isindependently selected from H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.12.-17. (canceled)
 18. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier. 19.-20.(canceled)
 21. A compound according to claim 1 of Formula (Ia):

or a pharmaceutically acceptable salt thereof.
 22. A compound accordingto claim 1 of Formula (Ib):

or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a compound of claim 2 and a pharmaceuticallyacceptable carrier.
 24. A pharmaceutical composition comprising acompound of claim 4 and a pharmaceutically acceptable carrier.
 25. Apharmaceutical composition comprising a compound of claim 5 and apharmaceutically acceptable carrier.
 26. A pharmaceutical compositioncomprising a compound of claim 6 and a pharmaceutically acceptablecarrier.
 27. A pharmaceutical composition comprising a compound of claim7 and a pharmaceutically acceptable carrier.
 28. A pharmaceuticalcomposition comprising a compound of claim 8 and a pharmaceuticallyacceptable carrier.
 29. A pharmaceutical composition comprising acompound of claim 9 and a pharmaceutically acceptable carrier.
 30. Apharmaceutical composition comprising a compound of claim 10 and apharmaceutically acceptable carrier.
 31. A pharmaceutical compositioncomprising a compound of claim 11 and a pharmaceutically acceptablecarrier.
 32. A pharmaceutical composition comprising a compound of claim21 and a pharmaceutically acceptable carrier.
 33. A pharmaceuticalcomposition comprising a compound of claim 22 and a pharmaceuticallyacceptable carrier.
 34. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 1. 35. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 2. 36. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 4. 37. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 5. 38. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 6. 39. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 7. 40. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 8. 41. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 9. 42. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 10. 43. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 11. 44. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 21. 45. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim 22.